Pyrazolopyridine derivatives as TTX-S blockers

ABSTRACT

The present invention relates to pyrazolopyridine derivatives which have blocking activities of voltage gated sodium channels as the TTX-S channels, and which are useful in the treatment or prevention of disorders and diseases in which voltage gated sodium channels are involved. The invention also relates to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which voltage gated sodium channels are involved.

TECHNICAL FIELD

The present invention relates to the pyrazolopyridine derivatives which are sodium channel blockers and have a number of therapeutic applications, particularly in the treatment of pain.

BACKGROUND ART

The pyrazolopyridine derivatives of the present invention are sodium channel blockers and have a number of therapeutic applications, particularly in the treatment of pain. More particularly, the pyrazolopyridine derivatives of the invention are selective tetrodotoxin-sensitive (TTX-S) blockers. In the discussion that follows, the invention is exemplified by reference to the inhibition of Na_(V1.3) or Na_(V1.7) channel as the TTX-S channels. They show the affinity for Na_(V1.3) or Na_(V1.7) channel which is significantly greater than their affinity for Na_(V1.5) channel as the tetrodotoxin-resistant (TTX-R) sodium channels. The pyrazolopyridine derivatives of the invention show good selectivity for the Na_(V1.3) or Na_(V1.7) channel as compared with Na_(V1.5) channel.

The rat Na_(V1.3) channel and the human Na_(V1.3) channel have been cloned in 1988, 1998, 2000 respectively (NPL 1, NPL 2, and NPL 3). The Na_(V1.3) channel was formerly known as brain type III sodium channel. Na_(V1.3) is present at relatively high levels in the nervous system of rat embryos but is barely detectable in adult rats. Na_(V1.3) is upregulated following axotomy in the Spinal Nerve Ligation (SNL), Chronic Constriction Injury (CCI), and diabetic neuropathy models (NPL 4, NPL 5, NPL 6, and NPL 7). The up-regulation of Na_(V1.3) channel contributes to rapidly repriming sodium current in small dorsal root ganglion (DRG) neurons (NPL 3). These observations suggest that Na_(V1.3) may make a key contribution to neuronal hyperexcitability.

In order to validate the contribution of Na_(V1.3) sodium channel in the pain states, specific antisense oligonucleotides (ASO) were used in animal pain models. Na_(V1.3) sodium channel ASO treatment significantly attenuated pain-related behaviors after CCI operation (NPL 8). These findings suggest that Na_(V1.3) sodium channel antagonist is useful to treat neuropathic pain conditions.

The Na_(V1.7) channel appears to be the best ‘validated’ pain target. The most exciting findings with respect to Na_(V1.7) have come from human genetic studies. Cox et al. (NPL 9) discovered SCN9A mutations that cause a loss of Na_(V1.7) function in three families from Pakistan. Their observations link loss of Na_(V1.7) function with a congenital inability to experience pain, adding to the evidence indicating Na_(V1.7) channel as an essential participant in human nociception.

By contrast, Gain-of-function mutations have also been described that lead to enhanced pain, for example, Primary Erythermalgia in one case and Paroxysmal Extreme Pain Disorder in another. These gain-of-function mutations in patients led to different types of gating changes in Na_(V1.7) sodium currents and, interestingly, different degrees of effectiveness of specific sodium channel blocking drugs. The implication from these findings is that a selective Na_(V1.7) blocker may be an effective treatment for pain in man.

A local anaesthetic lidocaine and a volatile anaesthetic halothane are known to act on both TTX-R and TTX-S sodium channels with poor selectivity and low potency (IC₅₀ values range from 50 microM to 10 mM). These anaesthetics at high systemic concentrations could cause devastating side effects, e.g., paralysis and cardiac arrest. However, systemic administration of lidocaine at low concentrations is effective to treat chronic pain (NPL 10). In rats, application of a very low dose of TTX to the DRG of the injured segment of the L5 spinal nerve significantly reduces mechanical allodynic behavior (NPL 11). This suggests that TTX-S subtypes of sodium channels play an important role in maintaining allodynic behaviors in an animal model of neuropathic pain.

The Na_(V1.5) channel is also a member of TTX-resistant sodium channels. The Na_(V1.5) channel is almost exclusively expressed in cardiac tissue and has been shown to underlie a variety of cardiac arrhythmias and conduction disorders.

CITATION LIST Non Patent Literature

{NPL 1} FEBS Lett. 228 (1), 187-194, 1988.

{NPL 2} J. Mol. Neurosci., 10 (1), 67-70, 1998.

{NPL 3} Eur. J. Neurosci. 12 (12), 4281-4289, 2000

{NPL 4} J Neurophysiol 82, 2776-2785, 1999. J. A. Black et al.

{NPL 5} Ann Neurol 52, 786-792, 2002. M. J. Cranner et al.

{NPL 6} J Biol Chem 279, 29341-29350, 2004. S. Hong et al.

{NPL 7} Mol Brain Res 95, 153-161, 2001. C. H. Kim et al.

{NPL 8} J. Neurosci. 24, 4832-4839, 2004, Hains, B. C. et al.

{NPL 9} Nature 444, 894-898, 2006.

{NPL 10} Trends in Pharm. Sci 22, 27-31, 2001, Baker, M. D. et al.

{NPL 11} Brain Res 871, 98-103, 2000, Lyu, Y. S. et al.

SUMMARY OF INVENTION Technical Problem

It is an objective of the invention to provide new TTX-S blockers that are good drug candidates. Preferred compounds should bind potently to the TTX-S(Na_(V1.3) and/or Na_(v1.7)) channels whilst showing little affinity for other sodium channels, particularly the Na_(V1.5) channel. They should be well absorbed from the gastrointestinal tract, be metabolically stable and possess favorable pharmacokinetic properties. They should be non-toxic and demonstrate few side-effects. Furthermore, the ideal drug candidate will exist in a physical form that is stable, non-hygroscopic and easily formulated.

In particular, the pyrazolopyridine derivatives of the present invention are selective for the TTX-S channels over the Na_(V1.5) channel, leading to improvements in the side-effect profile.

The pyrazolopyridine derivatives of the present invention are therefore useful in the treatment of a wide range of disorders, particularly pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain including post-surgical pain, and mixed pain types involving the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spine, urogenital system, cardiovascular system and CNS, including cancer pain, back pain, orofacial pain and chemo-induced pain.

Other conditions that may be treated with the pyrazolopyridine derivatives of the present invention include multiple sclerosis, neurodegenerative disorders, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, breakthrough pain, postsurgical pain, stroke, cancer pain, seizure disorder and causalgia.

The compounds showed activities against Na_(V1.3) or Na_(V1.7) channel. In addition they showed selectivity for the Na_(V1.3) or Na_(V1.7) channel as compared with Na_(V1.5) channel.

Solution to Problem

With respect to other compounds disclosed in the art, the compounds of the present invention may show less toxicity, good absorption and distribution, good solubility, less plasma protein binding, less drug-drug interaction, good metabolic stability, reduced inhibitory activity at HERG channel, and/or reduced QT prolongation.

[1] This invention provides a compound of the following formula (I):

Wherein:

-   A is aryl; preferable aryl is pyridyl, phenyl, pyrazinyl,     pyridazinyl, pyrazole, triazolyl, indolyl, benzimidazolyl, or     isoquinolinyl; more preferable aryl is pyridyl, phenyl, pyrazinyl,     or pyridazinyl; the most preferable aryl is pyridyl, or phenyl; -   B is selected from the group consisting of a chemical bond, —C₁₋₆     alkylene-, —C₁₋₆ alkylene-NR²—, —NR²—, and —(C═O)—; -   C is selected from the group consisting of a chemical bond, —(C═O)—,     and —NR²—; -   R¹ is independently selected from the group consisting of; -   (1) hydrogen, (2) —O_(n)—C₁₋₆ alkyl where the alkyl is unsubstituted     or substituted with one or more substituents independently selected     from R¹¹, (3) —O_(n)—C₃₋₇ cycloalkyl where the cycloalkyl is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹, (4) —O_(n)-aryl where the aryl is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹, (5) —S—C₁₋₆ alkyl, where the alkyl     is unsubstituted or substituted with one or more substituents     independently selected from R¹¹, (6) —S-aryl where the aryl is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹; (7) —NH—C₁₋₆ alkyl, where the alkyl     is unsubstituted or substituted with one or more substituents     independently selected from R¹¹, and (8) —NH-aryl, where the aryl is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹; -   preferable R¹ is independently selected from the group consisting     of; -   (2) —O_(n)—C₁₋₆ alkyl where the alkyl is unsubstituted or     substituted with one or more substituents independently selected     from R¹¹, (3) —O_(n)—C₃₋₇ cycloalkyl where the cycloalkyl is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹, (4) —O_(n)-aryl where the aryl is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹, and (7) —NH—C₁₋₆ alkyl, where the     alkyl is unsubstituted or substituted with one or more substituents     independently selected from R¹¹; -   wherein n is independently 0 or 1, when n is 0, a chemical bond is     present in the place of —O_(n)—; -   R² is independently selected from the group consisting of: -   (1) hydrogen, (2) halogen, (3) hydroxyl, (4) —O_(n)—C₁₋₆ alkyl,     where the alkyl is unsubstituted or substituted with one or more     substituents independently selected from R⁷, -   (5) —O_(n)—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or     substituted with one or more substituents independently selected     from R⁷, (6) —O_(n)—C₂₋₄ alkenyl, where the alkenyl is unsubstituted     or substituted with one or more substituents independently selected     from R⁷, (7) —O_(n)-phenyl or —O_(n)-naphthyl, where the phenyl or     naphthyl is unsubstituted or substituted with one or more     substituents independently selected from R⁷, (8)     —O_(n)-heterocyclyl, where the heterocyclyl is unsubstituted or     substituted with one or more substituents independently selected     from R⁷, (9) —(C═O)—NR⁸R⁹, (10) —NR⁸R⁹, (11) —S(O)₂—NR⁸R⁹, (12)     —NR⁸—S(O)₂R⁹, (13) —S(O)_(t)—R⁹, where t is 0, 1 or 2, (14) —NR⁸     (C═O)R⁹, (15) —CN, and (16) —NO₂; -   wherein n is independently 0 or 1, when n is 0, a chemical bond is     present in the place of —O_(n)—; preferable R² is independently     selected from the group consisting of: (1) hydrogen, (2)     halogen, (3) C₁₋₆ alkyl, and (4) —O—C₁₋₆ alkyl; more preferable R²     is independently selected from the group consisting of: (1)     hydrogen, (2) halogen, (3) methyl, and (4) methoxy; -   p is 1, 2, 3, or 4; when p is two or more than two, R² may be same     or different; preferable p is 1; -   R³ and R⁴ are independently hydrogen or C₁₋₆ alkyl which is     unsubstituted or substituted with one or more substituents     independently selected from halogen, hydroxyl, and —O—C₁₋₆ alkyl; or     R³ form a 3 to 7 membered ring with R⁴ which may contain nitrogen     atom, oxygen atom, sulfur atom or double bond, wherein the 3 to 7     membered ring is optionally substituted with 1 to 6 substituents     independently selected from the group consisting of: (1)     hydrogen, (2) hydroxyl, (3) halogen, (4) C₁₋₆ alkyl, which is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹, (5) C₃₋₆ cycloalkyl, which is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹, (6) —O—C₁₋₆ alkyl, where the alkyl     is unsubstituted or substituted with one or more substituents     independently selected from R¹¹, and (7) —O—C₃₋₆ cycloalkyl, where     the cycloalkyl is unsubstituted or substituted with one or more     substituents independently selected from R¹¹; preferable R³ is     hydrogen; preferable R⁴ is hydrogen or C₁₋₆ alkyl; more preferable     R⁴ is hydrogen or methyl; R⁵ is independently selected from the     group consisting of: -   (1) hydrogen, (2) halogen, (3) —O_(n)—C₁₋₆ alkyl, where the alkyl is     unsubstituted or substituted with one or more substituents     independently selected from R⁷, (4) —O_(n)—C₃₋₆ cycloalkyl, where     the cycloalkyl is unsubstituted or substituted with one or more     substituents independently selected from R⁷, and (5) —O_(n)—C₂₋₄     alkenyl, where the alkenyl is unsubstituted or substituted with one     or more substituents independently selected from R⁷; -   wherein n is independently 0 or 1, when n is 0, a chemical bond is     present in the place of —O_(n)—; preferable R⁵ is hydrogen or C₁₋₆     alkyl; more preferable R⁵ is hydrogen or methyl; -   R⁵ may be anywhere on the pyrazolopyridine ring; -   q is 1, 2 or 3; when q is two or more than two, R⁵ may be same or     different; preferable q is 1; -   R⁶ is independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl,     C₃₋₇ cycloalkyl, —NR⁸R⁹, heterocyclyl, aryl, aryl-C₁₋₆ alkyl, or     heterocyclyl-C₁₋₆ alkyl, where the C₁₋₆ alkyl, the C₁₋₆ alkoxy, the     C₂₋₆ alkenyl, the C₃₋₇ cycloalkyl, the heterocyclyl, the aryl, the     aryl-C₁₋₆ alkyl, or the heterocyclyl-C₁₋₆ alkyl, is unsubstituted or     substituted with one or more substituents independently selected     from halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —C₃₋₇ cycloalkyl,     —O—C₃₋₇ cycloalkyl, hydroxyl-C₁₋₆ alkoxy, —CN, —NR⁸R⁹, —(C═O)—R⁸,     —(C═O)—NR⁸R⁹, —NR⁸—(C═O)—R⁹, —NR⁸—(C═O)—NR⁹R ¹⁰, —NR⁸—(C═O)—OR⁹,     —NR⁸—S(O)₂—R⁹, —NR⁸—S(O)₂—NR⁹R¹⁰, and —S(O)₂—R⁸; -   when B is —NR²— and C is —(C═O)—, R⁶ may form the 4-7 membered ring     with R²; preferable R⁶ is independently hydrogen, C₁₋₆ alkyl, C₃₋₇     cycloalkyl, heterocyclyl, or aryl, where the C₁₋₆ alkyl, the C₃₋₇     cycloalkyl, the heterocyclyl, or the aryl, is unsubstituted or     substituted with one or more substituents independently selected     from halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —CN, —NR⁸R⁹, and     —NR⁸—(C═O)—R⁹; more preferable R⁶ is selected from the group     consisting of methyl, ethyl, isopropyl, and cyclopropyl,     heterocyclyl, or aryl which is unsubstituted or substituted with one     or more substituents independently selected from halogen, hydroxyl,     C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —CN; -   more preferable R⁶ is also selected from the group consisting of     methyl, ethyl, propyl, and cyclopropyl, which is unsubstituted or     substituted with one or more substituents independently selected     from halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —CN, —NR⁸R⁹, and     —NR⁸—(C═O)—R⁹; -   R⁷ is selected from the group consisting of: -   (1) hydrogen, (2) halogen, (3) hydroxyl, (4) —(C═O)_(m)—O_(l)—C₁₋₆     alkyl, where the alkyl is unsubstituted or substituted with one or     more substituents independently selected from R¹¹, (5)     —O_(l)—(C₁₋₃)perfluoroalkyl, (6) —(C═O)_(m)—O_(l)—C₃₋₆ cycloalkyl,     where the cycloalkyl is unsubstituted or substituted with one or     more substituents independently selected from R¹¹, (7)     —(C═O)_(m)—O_(l)—C₂₋₄alkenyl, where the alkenyl is unsubstituted or     substituted with one or more substituents independently selected     from R¹¹, (8) —(C═O)_(m)—O_(l)-phenyl or —(C═O)_(m)—O_(l)-naphthyl,     where the phenyl or naphthyl is unsubstituted or substituted with     one or more substituents independently selected from R¹¹, (9)     —(C═O)_(m)—O_(l)-heterocyclyl, where the heterocyclyl is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹, (10) —(C═O)—NR⁸R⁹, (11)     —NR⁸R⁹, (12) —S(O)₂—NR⁸R⁹, (13) —S(O)_(t)—R⁸, where t is 0, 1 or     2, (14) —CO₂H, (15) —CN, and (16) —NO₂; -   wherein l is 0 or 1 and m is 0 or 1; when l is 0 or m is 0, a     chemical bond is present in the place of —O_(l)— or —(C═O)_(m)—, and     when l is 0 and m is 0, a chemical bond is present in the place of     —(C═O)_(m)—O_(l)—; -   preferable R⁷ is hydrogen; -   R⁸, R⁹, and R¹⁰ are independently hydrogen, C₁₋₆ alkyl, C₂₋₆     alkenyl, C₃₋₇ cycloalkyl, or aryl, which is unsubstituted or     substituted with one or more substituents independently selected     from halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, C₃₋₇ cycloalkyl,     and —O—C₃₋₇ cycloalkyl; or R⁸ form a 4 to 7 membered ring with R⁹     which may contain nitrogen atom, oxygen atom, sulfur atom or double     bond, wherein the 4 to 7 membered ring is optionally substituted     with 1 to 6 substituents independently selected from the group     consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C₁₋₆     alkyl, which is unsubstituted or substituted with one or more     substituents independently selected from R¹¹, (5) C₃₋₆ cycloalkyl,     which is unsubstituted or substituted with one or more substituents     independently selected from R¹¹, (6) —O—C₁₋₆ alkyl, where the alkyl     is unsubstituted or substituted with one or more substituents     independently selected from R¹¹, and (7) —O—C₃₋₆ cycloalkyl, where     the cycloalkyl is unsubstituted or substituted with one or more     substituents independently selected from R¹¹; -   preferable R⁸, R⁹, and R¹⁰ are independently hydrogen, C₁₋₆ alkyl,     or C₃₋₇ cycloalkyl; -   R¹¹ is independently selected from the group consisting of: -   (1) hydrogen, (2) hydroxyl, (3) halogen, (4) —C₁₋₆ alkyl, which is     unsubstituted or substituted with one or more halogen, (5) —C₃₋₆     cycloalkyl, (6) —O—C₁₋₆ alkyl, where the alkyl is unsubstituted or     substituted with one or more halogen, (7) —O(C═O)—C₁₋₆ alkyl, (8)     —NH—C₁₋₆ alkyl, (9) phenyl, (10) heterocyclyl, (11) —CN, and (12)     —Si(C₁₋₆ alkyl)₃; -   preferable R¹¹ is halogen or —C₃₋₆ cycloalkyl; -   k is 1 or 2; preferable k is 1; -   r is 0 or 1, when r is 0, a chemical bond is present in the place of     —[O]_(r)—; preferable r is 0; -   or a prodrug thereof or a pharmaceutically acceptable salt thereof.

[2] This invention provides a compound represented by above formula (I) according to [1]

wherein:

k is 1;

r is 0;

or a prodrug thereof or a pharmaceutically acceptable salt thereof.

[3] Preferable compounds of this invention are represented by the following formula (II):

wherein:

-   A is aryl; preferable aryl is pyridyl, phenyl, pyrazinyl,     pyridazinyl, pyrazole, triazolyl, indolyl, benzimidazolyl, or     isoquinolinyl; more preferable aryl is pyridyl, phenyl, pyrazinyl,     or pyridazinyl; the most preferable aryl is pyridyl, or phenyl; -   R¹ is independently selected from the group consisting of: -   (1) hydrogen, (2) —O_(n)—C₁₋₆ alkyl where the alkyl is unsubstituted     or substituted with one or more substituents independently selected     from R¹¹, (3) —O_(n)—C₃₋₇ cycloalkyl where the cycloalkyl is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹, (4) —O_(n)-aryl where the aryl is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹, (5) —S—C₁₋₆ alkyl, where the alkyl     is unsubstituted or substituted with one or more substituents     independently selected from R¹¹, (6) —S-aryl where the aryl is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹; (7) —NH—C₁₋₆ alkyl, where the alkyl     is unsubstituted or substituted with one or more substituents     independently selected from R¹¹, and (8) —NH-aryl, where the aryl is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹; -   preferable R¹ is independently selected from the group consisting     of: -   (2) —O_(n)—C₁₋₆ alkyl where the alkyl is unsubstituted or     substituted with one or more substituents independently selected     from R¹¹, (3) —O_(n)—C₃₋₇ cycloalkyl where the cycloalkyl is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹, (4) —O_(n)-aryl where the aryl is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹ and (7) —NH—C₁₋₆ alkyl, where the     alkyl is unsubstituted or substituted with one or more substituents     independently selected from R¹¹; -   wherein n is independently 0 or 1, when n is 0, a chemical bond is     present in the place of —O_(n)—; -   R² is independently selected from the group consisting of: -   (1) hydrogen, (2) halogen, (3) hydroxyl, (4) —O_(n)—C₁₋₆ alkyl,     where the alkyl is unsubstituted or substituted with one or more     substituents independently selected from R⁷, (5) —O_(n)—C₃₋₆     cycloalkyl, where the cycloalkyl is unsubstituted or substituted     with one or more substituents independently selected from R⁷, (6)     —O_(n)—C₂₋₄ alkenyl, where the alkenyl is unsubstituted or     substituted with one or more substituents independently selected     from R⁷, (7) —O_(n)-phenyl or —O_(n)-naphthyl, where the phenyl or     naphthyl is unsubstituted or substituted with one or more     substituents independently selected from R⁷, (8)     —O_(n)-heterocyclyl, where the heterocyclyl is unsubstituted or     substituted with one or more substituents independently selected     from R⁷, (9) —(C═O)—NR⁸R⁹, (10) —NR⁸R⁹, (11) —S(O)₂—NR⁸R⁹, (12)     —NR⁸—S(O)₂R⁹, (13) —S(O)_(t)—R⁹, where t is 0, 1 or 2, (14) —NR⁸     (C═O)R⁹, (15) —CN, and (16) —NO₂; -   wherein n is independently 0 or 1, when n is 0, a chemical bond is     present in the place of —O_(n)—; -   preferable R² is independently selected from the group consisting     of: (1) hydrogen, (2) halogen, (3) C₁₋₆ alkyl, and (4) —O—C₁₋₆     alkyl; more preferable R² is independently selected from the group     consisting of: (1) hydrogen, (2) halogen, (3) methyl, and (4)     methoxy; -   p is 1, 2, 3, or 4; when p is two or more than two, R² may be same     or different; preferable p is 1; -   R³ and R⁴ are independently hydrogen or C₁₋₆ alkyl which is     unsubstituted or substituted with one or more substituents     independently selected from halogen, hydroxyl, and —O—C₁₋₆ alkyl; or     R³ form a 3 to 7 membered ring with R⁴ which may contain nitrogen     atom, oxygen atom, sulfur atom or double bond, wherein the 3 to 7     membered ring is optionally substituted with 1 to 6 substituents     independently selected from the group consisting of: (1)     hydrogen, (2) hydroxyl, (3) halogen, (4) C₁₋₆ alkyl, which is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹, (5) C₃₋₆ cycloalkyl, which is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹, (6) —O—C₁₋₆ alkyl, where the alkyl     is unsubstituted or substituted with one or more substituents     independently selected from R¹¹, and (7) —O—C₃₋₆ cycloalkyl, where     the cycloalkyl is unsubstituted or substituted with one or more     substituents independently selected from R¹¹; -   preferable R³ is hydrogen; preferable R⁴ is hydrogen or C₁₋₆ alkyl;     more preferable R⁴ is hydrogen or methyl; -   R⁵ is independently selected from the group consisting of: -   (1) hydrogen, (2) halogen, (3) —O_(n)—C₁₋₆ alkyl, where the alkyl is     unsubstituted or substituted with one or more substituents     independently selected from R⁷, (4) —O_(n)—C₃₋₆ cycloalkyl, where     the cycloalkyl is unsubstituted or substituted with one or more     substituents independently selected from R⁷, and (5) —O_(n)—C₂₋₄     alkenyl, where the alkenyl is unsubstituted or substituted with one     or more substituents independently selected from R⁷; -   wherein n is independently 0 or 1, when n is 0, a chemical bond is     present in the place of —O_(n)—; -   preferable R⁵ is hydrogen or C₁₋₆ alkyl; more preferable R⁵ is     hydrogen or methyl; -   R⁵ may be anywhere on the pyrazolopyridine ring; -   q is 1, 2 or 3; when q is two or more than two, R⁵ may be same or     different; preferable q is 1; -   R⁶ is independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl,     C₃₋₇ cycloalkyl, —NR⁸R⁹, heterocyclyl, aryl, aryl-C₁₋₆ alkyl, or     heterocyclyl-C₁₋₆ alkyl, where the C₁₋₆ alkyl, the C₁₋₆ alkoxy, the     C₂₋₆ alkenyl, the C₃₋₇ cycloalkyl, the heterocyclyl, the aryl, the     aryl-C₁₋₆ alkyl, or the heterocyclyl-C₁₋₆ alkyl, is unsubstituted or     substituted with one or more substituents independently selected     from halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —C₃₋₇ cycloalkyl,     —O—C₃₋₇ cycloalkyl, hydroxyl-C₁₋₆ alkoxy, —CN, —NR⁸R⁹, —(C═O)—R⁸,     —(C═O)—NR⁸R⁹, —NR⁸—(C═O)—R⁹, —NR⁸—(C═O)—NR⁹R¹⁰, —NR⁸—S(O)₂—R⁹,     —NR⁸—S(O)₂—NR⁹R¹⁰, and —S(O)₂—R⁸; -   preferable R⁶ is independently hydrogen, C₁₋₆ alkyl, C₃₋₇     cycloalkyl, heterocyclyl, or aryl, where the C₁₋₆ alkyl, the C₃₋₇     cycloalkyl, the heterocyclyl, or the aryl, is unsubstituted or     substituted with one or more substituents independently selected     from halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —CN, —NR⁸R⁹, and     —NR⁸—(C═O)—R⁹; more preferable R⁶ is selected from the group     consisting of methyl, ethyl, isopropyl, and cyclopropyl,     heterocyclyl, or aryl which is unsubstituted or substituted with one     or more substituents independently selected from halogen, hydroxyl,     C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —CN; -   R⁷ is selected from the group consisting of: -   (1) hydrogen, (2) halogen, (3) hydroxyl, (4) —(C═O)_(m)—O_(l)—C₁₋₆     alkyl, where the alkyl is unsubstituted or substituted with one or     more substituents independently selected from R¹¹, (5)     —O_(l)—(C₁₋₃)perfluoroalkyl, (6) —(C═O)_(m)—O_(l)—C₃₋₆ cycloalkyl,     where the cycloalkyl is unsubstituted or substituted with one or     more substituents independently selected from R¹¹, (7)     —(C═O)_(m)—O_(l)—C₂₋₄alkenyl, where the alkenyl is unsubstituted or     substituted with one or more substituents independently selected     from R¹¹, (8) —(C═O)_(m)—O_(l)-phenyl or —(C═O)_(m)—O_(l)-naphthyl,     where the phenyl or naphthyl is unsubstituted or substituted with     one or more substituents independently selected from R¹¹, (9)     —(C═O)_(m)—O_(l)-heterocyclyl, where the heterocyclyl is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹, (10) —(C═O)—NR⁸R⁹, (11)     —NR⁸R⁹, (12) —S(O)₂—NR⁸R⁹, (13) —S(O)_(t)—R⁸, where t is 0, 1 or     2, (14) —CO₂H, (15) —CN, and (16) —NO₂; -   wherein l is 0 or 1 and m is 0 or 1; when l is 0 or m is 0, a     chemical bond is present in the place of —O_(r) or —(C═O)_(m)—, and     when l is 0 and m is 0, a chemical bond is present in the place of     —(C═O)_(m)—O_(l)—; -   preferable R⁷ is hydrogen; -   R⁸, R⁹, and R¹⁰ are independently hydrogen, C₁₋₆ alkyl, C₂₋₆     alkenyl, C₃₋₇ cycloalkyl, or aryl, which is unsubstituted or     substituted with one or more substituents independently selected     from halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, C₃₋₇ cycloalkyl,     and —O—C₃₋₇ cycloalkyl; or R⁸ form a 4 to 7 membered ring with R⁹     which may contain nitrogen atom, oxygen atom, sulfur atom or double     bond, wherein the 4 to 7 membered ring is optionally substituted     with 1 to 6 substituents independently selected from the group     consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C₁₋₆     alkyl, which is unsubstituted or substituted with one or more     substituents independently selected from R¹¹, (5) C₃₋₆ cycloalkyl,     which is unsubstituted or substituted with one or more substituents     independently selected from R¹¹, (6) —O—C₁₋₆ alkyl, where the alkyl     is unsubstituted or substituted with one or more substituents     independently selected from R¹¹, and (7) —O—C₃₋₆ cycloalkyl, where     the cycloalkyl is unsubstituted or substituted with one or more     substituents independently selected from R¹¹; -   preferable R⁸, R⁹, and R¹⁰ are independently hydrogen, C₁₋₆ alkyl,     or C₃₋₇ cycloalkyl; R¹¹ is independently selected from the group     consisting of: -   (1) hydrogen, (2) hydroxyl, (3) halogen, (4) —C₁₋₆ alkyl, which is     unsubstituted or substituted with one or more halogen, (5) —C₃₋₆     cycloalkyl, (6) —O—C₁₋₆ alkyl, where the alkyl is unsubstituted or     substituted with one or more halogen, (7) —O(C═O)—C₁₋₆ alkyl, (8)     —NH—C₁₋₆ alkyl, (9) phenyl, (10) heterocyclyl, (11) —CN, and (12)     —Si(C₁₋₆ alkyl)₃; preferable R¹¹ is halogen or —C₃₋₆ cycloalkyl; -   or a prodrug thereof or a pharmaceutically acceptable salt thereof.

[4] Compounds described in [3] are further preferred wherein:

R² is independently selected from the group consisting of:

(1) hydrogen, (2) halogen, (3) methyl, and (4) methoxy;

p is 1;

R³ is hydrogen;

R⁴ is hydrogen or methyl;

R⁶ is selected from the group consisting of methyl, ethyl, isopropyl, and cyclopropyl, heterocyclyl, or aryl which is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —CN;

or a prodrug thereof or a pharmaceutically acceptable salt thereof.

[5] Preferable compounds of this invention are represented by the following formula (III):

-   wherein: -   A is aryl; preferable aryl is pyridyl, phenyl, pyrazinyl,     pyridazinyl, pyrazole, triazolyl, indolyl, benzimidazolyl, or     isoquinolinyl; more preferable aryl is pyridyl, phenyl, pyrazinyl,     or pyridazinyl; the most preferable aryl is pyridyl, or phenyl; -   R¹ is independently selected from the group consisting of; -   (1) hydrogen, (2) —O_(n)—C₁₋₆ alkyl where the alkyl is unsubstituted     or substituted with one or more substituents independently selected     from R¹¹, (3) —O_(n)—C₃₋₇ cycloalkyl where the cycloalkyl is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹, (4) —O_(n)-aryl where the aryl is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹, (5) —S—C₁₋₆ alkyl, where the alkyl     is unsubstituted or substituted with one or more substituents     independently selected from R¹¹, (6) —S-aryl where the aryl is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹; (7) —NH—C₁₋₆ alkyl, where the alkyl     is unsubstituted or substituted with one or more substituents     independently selected from R¹¹, and (8) —NH-aryl, where the aryl is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹; -   preferable R¹ is independently selected from the group consisting     of; -   (2) —O_(n)—C₁₋₆ alkyl where the alkyl is unsubstituted or     substituted with one or more substituents independently selected     from R¹¹, (3) —O_(n)—C₃₋₇ cycloalkyl where the cycloalkyl is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹, (4) —O_(n)-aryl where the aryl is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹ and (7) —NH—C₁₋₆ alkyl, where the     alkyl is unsubstituted or substituted with one or more substituents     independently selected from R¹¹; -   wherein n is independently 0 or 1, when n is 0, a chemical bond is     present in the place of —O_(n)—; -   R² is independently selected from the group consisting of: -   (1) hydrogen, (2) halogen, (3) hydroxyl, (4) —O_(n)—C₁₋₆ alkyl,     where the alkyl is unsubstituted or substituted with one or more     substituents independently selected from R⁷, (5) —O_(n)—C₃₋₆     cycloalkyl, where the cycloalkyl is unsubstituted or substituted     with one or more substituents independently selected from R⁷, (6)     —O_(n)—C₂₋₄ alkenyl, where the alkenyl is unsubstituted or     substituted with one or more substituents independently selected     from R⁷, (7) —O_(n)-phenyl or —O_(n)-naphthyl, where the phenyl or     naphthyl is unsubstituted or substituted with one or more     substituents independently selected from R⁷, (8)     —O_(n)-heterocyclyl, where the heterocyclyl is unsubstituted or     substituted with one or more substituents independently selected     from R⁷, (9) —(C═O)—NR⁸R⁹, (10) —NR⁸R⁹, (11) —S(O)₂—NR⁸R⁹, (12)     —NR⁸—S(O)₂R⁹, (13) —S(O)_(t)—R⁹, where t is 0, 1 or 2, (14) —NR⁸     (C═O)R⁹, (15) —CN, and (16) —NO₂; -   wherein n is independently 0 or 1, when n is 0, a chemical bond is     present in the place of —O_(n)—; preferable R² is independently     selected from the group consisting of: (1) hydrogen, (2)     halogen, (3) C₁₋₆ alkyl, and (4) —O—C₁₋₆ alkyl; more preferable R²     is independently selected from the group consisting of: (1)     hydrogen, (2) halogen, (3) methyl, and (4) methoxy; -   p is 1, 2, 3, or 4; when p is two or more than two, R² may be same     or different; preferable p is 1; -   R³ and R⁴ are independently hydrogen or C₁₋₆ alkyl which is     unsubstituted or substituted with one or more substituents     independently selected from halogen, hydroxyl, and —O—C₁₋₆ alkyl; or     R³ form a 3 to 7 membered ring with R⁴ which may contain nitrogen     atom, oxygen atom, sulfur atom or double bond, wherein the 3 to 7     membered ring is optionally substituted with 1 to 6 substituents     independently selected from the group consisting of: (1)     hydrogen, (2) hydroxyl, (3) halogen, (4) C₁₋₆ alkyl, which is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹, (5) C₃₋₆ cycloalkyl, which is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹, (6) —O—C₁₋₆ alkyl, where the alkyl     is unsubstituted or substituted with one or more substituents     independently selected from R¹¹, and (7) —O—C₃₋₆ cycloalkyl, where     the cycloalkyl is unsubstituted or substituted with one or more     substituents independently selected from R¹¹; -   preferable R³ is hydrogen; preferable R⁴ is hydrogen or C₁₋₆ alkyl;     more preferable R⁴ is hydrogen or methyl; -   R⁵ is independently selected from the group consisting of: -   (1) hydrogen, (2) halogen, (3) —O_(n)—C₁₋₆ alkyl, where the alkyl is     unsubstituted or substituted with one or more substituents     independently selected from R⁷, (4) —O_(n)—C₃₋₆ cycloalkyl, where     the cycloalkyl is unsubstituted or substituted with one or more     substituents independently selected from R⁷, and (5) —O_(n)—C₂₋₄     alkenyl, where the alkenyl is unsubstituted or substituted with one     or more substituents independently selected from R⁷; -   wherein n is independently 0 or 1, when n is 0, a chemical bond is     present in the place of —O_(n)—; -   preferable R⁵ is hydrogen or C₁₋₆ alkyl; more preferable R⁵ is     hydrogen or methyl; R⁵ may be anywhere on the pyrazolopyridine ring; -   q is 1, 2 or 3; when q is two or more than two, R⁵ may be same or     different; preferable -   q is 1; -   R⁶ is independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl,     C₃₋₇ cycloalkyl, heterocyclyl, aryl, aryl-C₁₋₆ alkyl, or     heterocyclyl-C₁₋₆ alkyl, where the C₁₋₆ alkyl, the C₁₋₆ alkoxy, the     C₂₋₆ alkenyl, the C₃₋₇ cycloalkyl, the heterocyclyl, the aryl, the     aryl-C₁₋₆ alkyl, or the heterocyclyl-C₁₋₆ alkyl, is unsubstituted or     substituted with one or more substituents independently selected     from halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —C₃₋₇ cycloalkyl,     —O—C₃₋₇ cycloalkyl, hydroxyl-C₁₋₆ alkoxy, —CN, —NR⁸R⁹, —(C═O)—R⁸,     —(C═O)—NR⁸R⁹, —NR⁸—(C═O)—R⁹, —NR⁸—(C═O)—NR⁹R¹⁰, —NR⁸—(C═O)—OR⁹,     —NR⁸—S(O)₂—R⁹, —NR⁸—S(O)₂—NR⁹R¹⁰, and —S(O)₂—R⁸; preferable R⁶ is     independently hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,     or aryl, where the C₁₋₆ alkyl, the C₃₋₇ cycloalkyl, the     heterocyclyl, or the aryl, is unsubstituted or substituted with one     or more substituents independently selected from halogen, hydroxyl,     C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —CN, —NR⁸R⁹, and —NR⁸—(C═O)—R⁹; more     preferable R⁶ is selected from the group consisting of methyl,     ethyl, propyl, and cyclopropyl, which is unsubstituted or     substituted with one or more substituents independently selected     from halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —CN, —NR⁸R⁹, and     —NR⁸—(C═O)—R⁹; -   R⁷ is selected from the group consisting of: -   (1) hydrogen, (2) halogen, (3) hydroxyl, (4) —(C═O)_(m)—O_(l)—C₁₋₆     alkyl, where the alkyl is unsubstituted or substituted with one or     more substituents independently selected from R¹¹, (5)     —O_(l)—(C₁₋₃)perfluoroalkyl, (6) —(C═O)_(m)—O_(l)—C₃₋₆ cycloalkyl,     where the cycloalkyl is unsubstituted or substituted with one or     more substituents independently selected from R¹¹, (7)     —(C═O)_(m)—O_(l)—C₂₋₄alkenyl, where the alkenyl is unsubstituted or     substituted with one or more substituents independently selected     from R¹¹, (8) —(C═O)_(m)—O_(l)-phenyl or —(C═O)_(m)—O_(l)-naphthyl,     where the phenyl or naphthyl is unsubstituted or substituted with     one or more substituents independently selected from R¹¹, (9)     —(C═O)_(m)—O_(l)-heterocyclyl, where the heterocyclyl is     unsubstituted or substituted with one or more substituents     independently selected from R¹¹, (10) —(C═O)—NR⁸R⁹, (11)     —NR⁸R⁹, (12) —S(O)₂—NR⁸R⁹, (13) —S(O)—R⁸, where t is 0, 1 or 2, (14)     —CO₂H, (15) —CN, and (16) —NO₂; -   wherein l is 0 or 1 and m is 0 or 1; when l is 0 or m is 0, a     chemical bond is present in the place of —O_(r) or —(C═O)_(m)—, and     when l is 0 and m is 0, a chemical bond is present in the place of     —(C═O)_(m)—O_(l)—; -   preferable R⁷ is hydrogen; -   R⁸, R⁹, and R¹⁰ are independently hydrogen, C₁₋₆ alkyl, C₂₋₆     alkenyl, C₃₋₇ cycloalkyl, or aryl, which is unsubstituted or     substituted with one or more substituents independently selected     from halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, C₃₋₇ cycloalkyl,     and —O—C₃₋₇ cycloalkyl; or R⁸ form a 4 to 7 membered ring with R⁹     which may contain nitrogen atom, oxygen atom, sulfur atom or double     bond, wherein the 4 to 7 membered ring is optionally substituted     with 1 to 6 substituents independently selected from the group     consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C₁₋₆     alkyl, which is unsubstituted or substituted with one or more     substituents independently selected from R¹¹, (5) C₃₋₆ cycloalkyl,     which is unsubstituted or substituted with one or more substituents     independently selected from R¹¹, (6) —O—C₁₋₆ alkyl, where the alkyl     is unsubstituted or substituted with one or more substituents     independently selected from R¹¹, and (7) —O—C₃₋₆ cycloalkyl, where     the cycloalkyl is unsubstituted or substituted with one or more     substituents independently selected from R¹¹; -   preferable R⁸, R⁹, and R¹⁰ are independently hydrogen, C₁₋₆ alkyl,     or C₃₋₇ cycloalkyl; -   R¹¹ is independently selected from the group consisting of: -   (1) hydrogen, (2) hydroxyl, (3) halogen, (4) —C₁₋₆ alkyl, which is     unsubstituted or substituted with one or more halogen, (5) —C₃₋₆     cycloalkyl, (6) —O—C₁₋₆ alkyl, where the alkyl is unsubstituted or     substituted with one or more halogen, (7) —O(C═O)—C₁₋₆ alkyl, (8)     —NH—C₁₋₆ alkyl, (9) phenyl, (10) heterocyclyl, (11) —CN, and (12)     —Si(C₁₋₆ alkyl)₃; -   preferable R¹¹ is halogen or —C₃₋₆ cycloalkyl; -   or a prodrug thereof or a pharmaceutically acceptable salt thereof.

[6] Compounds described in [5] are further preferred wherein:

R² is independently selected from the group consisting of:

(1) hydrogen, (2) halogen, (3) methyl, and (4) methoxy;

p is 1;

R³ is hydrogen;

R⁴ is hydrogen or methyl;

R⁶ is selected from the group consisting of methyl, ethyl, isopropyl, propyl, or butyl which is unsubstituted or substituted with one or more substituents independently selected from hydroxyl, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, —O—C₁₋₆ alkyl, —CN, and —NR⁸—(C═O)—R⁹ in which each of R⁸ and R⁹ has the same meaning as above;

or a prodrug thereof or a pharmaceutically acceptable salt thereof.

[7] Suitable individual compounds of the invention are:

-   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-isobutyramide; -   2-hydroxy-2-methyl-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-acetamide; -   N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-isobutyramide; -   N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-acetamide; -   N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-propionamide; -   N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-cyclopropanecarboxamide; -   N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-acetamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-propionamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-isobutyramide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-tetrahydro-2H-pyran-4-carboxamide; -   N-(2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-cyclopropanecarboxamide; -   N-(2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-isobutyramide; -   N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-isobutyramide; -   N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-propionamide; -   N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-tetrahydro-2H-pyran-4-carboxamide; -   N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-acetamide; -   N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-propionamide; -   N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-isobutyramide; -   N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-acetamide; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-tetrahydro-2H-pyran-4-carboxamide; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-oxazole-5-carboxamide; -   1,1-dimethyl-3-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)urea; -   2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-amine; -   3-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-oxazolidin-2-one; -   ethyl-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-carbamate; -   N-(2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)acetamide; -   N-(2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-propionamide; -   4-methoxy-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine; -   2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-isopropyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-cyclopropanecarboxamide; -   N-(2-((6-(2,2-difluoroethoxy)-5-fluoropyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-cyclopropanecarboxamide; -   N-(2-((6-(2,2-difluoroethoxy)-5-fluoropyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-isobutyramide; -   N-(2-((6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-isobutyramide; -   N-(2-((6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-cyclopropanecarboxamide; -   N-(2-((5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-isobutyramide; -   N-(2-((5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-cyclopropanecarboxamide; -   N-(2-((6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-isobutyramide; -   N-(2-((6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-cyclopropanecarboxamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-isobutyramide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-cyclopropanecarboxamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-acetamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-propionamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-tetrahydro-2H-pyran-4-carboxamide; -   N-(2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-propionamide; -   N-(2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-cyclopropanecarboxamide; -   N-(2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-isobutyramide; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-pivalamide; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-nicotinamide; -   1-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-pyrrolidin-2-one; -   1-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-imidazolidin-2-one; -   4-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-morpholine; -   N-(1-methyl-1H-pyrazol-3-yl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-amine; -   2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(pyrimidin-2-yl)-2H-pyrazolo[4,3-c]-pyridin-4-amine; -   N-(2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-cyclopropanecarboxamide; -   N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-tetrahydro-2H-pyran-4-carboxamide; -   3-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-1,1-dimethylurea; -   N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-pivalamide; -   N-(2-(4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-(4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-cyclopropanecarboxamide; -   2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-4-(1H-pyrazol-5-yl)-2H-pyrazolo[4,3-c]pyridine; -   N-(2-((6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-((6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-cyclopropanecarboxamide; -   N-(2-(4-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   (S)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(tetrahydrofuran-3-yl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-cyclopropyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-cyclobutyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-(cyclopropylmethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-((tetrahydro-2H-pyran-4-yl)-methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-methoxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-N-(1-hydroxypropan-2-yl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridin-4-yl)propionamide; -   N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-isobutyramide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-cyclopropanecarboxamide; -   N-(2-(2-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((6-(4-fluorophenoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-isobutyramide; -   N-(2-((6-(4-fluorophenoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-cyclopropanecarboxamide; -   N-methyl-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridin-4-yl)isobutyramide; -   (S)-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)tetrahydrofuran-2-carboxamide; -   (S)-N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)tetrahydrofuran-2-carboxamide; -   N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-nicotinamide; -   (R)-2-hydroxy-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; -   (S)-2-hydroxy-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-pyrrolidine-1-carboxamide; -   1-acetyl-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridin-4-yl)piperidine-4-carboxamide; -   N-isopropyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-propyl-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-isobutyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-(2-ethoxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(cyanomethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-((tetrahydrofuran-2-yl)-methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-(dimethylamino)ethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(pyridin-3-ylmethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(pyridin-3-yl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)tetrahydrofuran-2-carboxamide; -   (R)-N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)tetrahydrofuran-2-carboxamide; -   N-(3-methoxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-((1-hydroxycyclohexyl)methyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridin-4-yl)propionamide; -   N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridin-4-yl)cyclopropanecarboxamide; -   N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridin-4-yl)isobutyramide; -   2-hydroxy-2-methyl-N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; -   N-(7-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridin-4-yl)propionamide; -   N-(7-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridin-4-yl)isobutyramide; -   2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   1-isobutyryl-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)piperidine-4-carboxamide; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-1-(methylsulfonyl)piperidine-4-carboxamide; -   (S)-1-acetyl-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)pyrrolidine-2-carboxamide; -   (R)-1-acetyl-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)pyrrolidine-2-carboxamide; -   N-methyl-N-(2-((2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)amino)-2-oxoethyl)acetamide; -   (S)-2-methoxy-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; -   (S)-N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-methoxypropanamide; -   (R)-N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxypropanamide; -   (S)-N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxypropanamide; -   2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-cyclopropyl-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-(cyclopropylmethyl)-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-morpholinoethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-(pyridin-2-yl)acetamide; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-(pyridin-3-yl)acetamide; -   N-isopropyl-2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-cyclopropyl-2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(cyclopropylmethyl)-2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-(pyridin-4-yl)acetamide; -   N-(cyanomethyl)-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-propyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-cyanopropan-2-yl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxy-2-methylpropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-(dimethylamino)propyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-aminoethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(oxetan-3-yl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-((4-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-ethyl-2-((4-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-(pyridin-4-yl)acetamide; -   2-(pyridin-4-yl)-N-(2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)acetamide; -   N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-(pyridin-3-yl)acetamide; -   2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((4-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-isobutyramide; -   N-(2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-cyclopropanecarboxamide; -   2-hydroxy-2-methyl-N-(2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; -   N-methyl-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-ethyl-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-isopropyl-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-(2-methylthiazol-4-yl)acetamide; -   N-(2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-(pyridin-3-yl)acetamide; -   N-(2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-(pyridin-4-yl)acetamide; -   2-(3,5-dimethylisoxazol-4-yl)-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)acetamide; -   N-isopropyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   (R)-N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-N-(2,3-dihydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-cyclopropanecarboxamide; -   2-hydroxy-2-methyl-N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; -   N-methyl-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-ethyl-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-N-(1-hydroxypropan-2-yl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-amino-2-oxoethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-(methylsulfonamido)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-cyanoethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-cyanoethyl)-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   2-((5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-ethyl-2-((5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-isopropyl-2-((5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-(2-hydroxyethoxy)ethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-isobutyramide; -   N-ethyl-2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   (R)-N-(2,3-dihydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(4-fluorophenoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-((6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   (S)-N-(1-amino-1-oxopropan-2-yl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-(methylamino)-2-oxoethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-amino-3-oxopropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxy-2,2-dimethylpropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-(4-hydroxybutyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-acetamidopropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-(methylsulfonamido)     propyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   2-(4-((2,2-difluoroethoxy)-3-methylbenzyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-((2,2-difluoroethoxy)-3-methylbenzyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-isobutyramide; -   N-(2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-cyclopropanecarboxamide; -   N-(3-hydroxypropyl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(4-fluorophenoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-methyl-2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-ethyl-2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-isobutyramide; -   N-(2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-cyclopropanecarboxamide; -   (S)-N-(2-hydroxypropyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-N-(2-hydroxypropyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-N-(2,3-dihydroxypropyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-N-(2,3-dihydroxypropyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-N-(2,3-dihydroxypropyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-((1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-ethyl-2-((1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   (S)-N-(2-hydroxypropyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-N-(2-hydroxypropyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-N-(1-hydroxypropan-2-yl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-N-(1-hydroxypropan-2-yl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-cyanoethyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-cyanoethyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-amino-2-oxoethyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-methoxyethyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((5-methyl-6-(2-(2,2,2-trifluoroethoxy)ethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridin-4-yl)isobutyramide; -   N-(2-((5-methyl-6-(2-(2,2,2-trifluoroethoxy)ethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridin-4-yl)cyclopropanecarboxamide; -   2-hydroxy-2-methyl-N-(2-((5-methyl-6-(2-(2,2,2-trifluoroethoxy)ethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; -   N-(2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-hydroxyethyl)-2-((5-methyl-6-(2-(2,2,2-trifluoroethoxy)ethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((5-methyl-6-(2-(2,2,2-trifluoroethoxy)ethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-((5-methyl-6-(2-(2,2,2-trifluoroethoxy)ethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((5-methyl-6-(2-(2,2,2-trifluoroethoxy)ethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide;     2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-ethyl-2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-isopropyl-2-((5-methyl-6-(2-(2,2,2-trifluoroethoxy)ethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-methyl-2-(2-(4-(trifluoromethyl)phenoxy)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-(2-(4-(trifluoromethyl)phenoxy)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-(2-(4-(trifluoromethyl)phenoxy)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(2-(4-(trifluoromethyl)phenoxy)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(2-(4-(trifluoromethyl)phenoxy)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-isobutyramide; -   N-(2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-isobutyramide; -   N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-cyclopropanecarboxamide; -   N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   2-(2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-N-methyl-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   2-(2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-N-isopropyl-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   2-(2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-cyclopropyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   2-((5-cyclopropyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   2-((5-cyclopropyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-cyclopropyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-cyclopropyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-ethyl-2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-isopropyl-2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-ethyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]-pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-((5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-methoxyethyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; -   N-(2-((5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-cyclopropanecarboxamide; -   N-(2-((6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-isobutyramide; -   N-(2-((6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-cyclopropanecarboxamide; -   N-(2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyrdin-4-yl)cyclopropanecarboxamide; -   N-(2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   N,6-dimethyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-((6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-(3-methyl-4-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-(3-methyl-4-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(3-methyl-4-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(3-methyl-4-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((5-phenyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-methyl-2-(3-methyl-4-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(4-fluorophenoxy)-5-methylpyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((6-(4-fluorophenoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-N-(3-(methylsulfonyl)propyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-((1-(2,2,2-trifluoroethoxy)isoquinolin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((1-(2,2,2-trifluoroethoxy)isoquinolin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((1-(2,2,2-trifluoroethoxy)isoquinolin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((1-(2,2,2-trifluoroethoxy)isoquinolin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((1-(2,2,2-trifluoroethoxy)isoquinolin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-(4-((2,2,2-trifluoroethoxy)methyl)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(4-((2,2,2-trifluoroethoxy)methyl)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-(4-((2,2,2-trifluoroethoxy)methyl)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-4-hydroxy-1-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)pyrrolidin-2-one; -   2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-((1-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((1-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((1-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((1-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((5-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-(methylsulfonyl)propyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((5-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((5-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((5-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((5-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((1-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((5-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   N-(2-(3-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(3-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   2-hydroxy-2-methyl-N-(2-(3-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; -   N-(2-(2-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(2-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-methyl-2-(3-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-(3-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(3-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(3-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-(2-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(2-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(2-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((5-(2,2,3,3,3-pentafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-(2,2,3,3,3-pentafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-hydroxyethyl)-2-(4-(1,1,2,2-tetrafluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(4-(1,1,2,2-tetrafluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((5-(2,2,3,3,3-pentafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((5-(2,2,3,3,3-pentafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((5-(2,2,3,3,3-pentafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   N-(2-((5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-acetamidoethyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-N-(2,3-dihydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-(3-(trifluoromethyl)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(3-(trifluoromethyl)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-methyl-2-(3-(trifluoromethyl)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-(3-(trifluoromethyl)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-(3-(trifluoromethyl)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(3-(trifluoromethyl)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-N-(2,3-dihydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)     methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-(4-(1,1,2,2-tetrafluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-(4-(1,1,2,2-tetrafluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-((S)-2-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2,3-dihydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2,3-dihydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(1-hydroxypropan-2-yl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   2-hydroxy-2-methyl-N-(2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; -   N-methyl-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-N-(1-hydroxypropan-2-yl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   N-(2-((1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-methyl-2-((1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-(4-((2,2-difluoroethoxy)-3-methylbenzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-(4-((2,2-difluoroethoxy)-3-methylbenzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(4-((2,2-difluoroethoxy)-3-methylbenzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   2-hydroxy-2-methyl-N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; -   2-hydroxy-2-methyl-N-(2-(3-methyl-4-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; -   2-hydroxy-2-methyl-N-(2-(2-(4-(trifluoromethyl)phenoxy)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; -   N-(2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-propionamidoethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-isobutyramidoethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-(cyclopropanecarboxamido)ethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   ethyl(2-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamido)ethyl)carbamate; -   N-(2-benzamidoethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-(2-hydroxy-2-methylpropanamido)ethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-(N-methylacetamido)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-butyramidoethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-(cyclobutanecarboxamido)ethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-(cyclohexanecarboxamido)ethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-(3-ethylureido)ethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(3-methyl-4-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(4-((2,2-difluoroethoxy)-3-methylbenzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((1-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-hydroxy-2-methyl-N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; -   2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-(picolinamido)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-(nicotinamido)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-(isonicotinamido)ethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-(1-hydroxycyclohexanecarboxamido)ethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)     pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   2-hydroxy-2-methyl-N-(2-((4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; -   N-(2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   N-methyl-2-((4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(2-(4-(trifluoromethyl)phenoxy)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((1-(2,2,2-trifluoroethoxy)isoquinolin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(4-(1,1,2,2-tetrafluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-((6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   2-((6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   N-(2-((4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   (R)-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(1-hydroxypropan-2-yl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(2,3-dihydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(2,3-dihydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-cyanoethyl)-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)oxazole-5-carboxamide; -   2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; -   (S)-2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-((R)-2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-2-(4-(2,2-difluoroethoxy)-3,5-dimethylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-2-(3-(2,2-difluoroethoxy)-4-methylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-((R)-2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-((R)-2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-((S)-2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-2-(4-(2,2-difluoroethoxy)-3,5-dimethylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-2-(3-(2,2-difluoroethoxy)-4-methylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-((S)-2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-((S)-2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-(2,2-difluoroethoxy)-3,5-dimethylbenzyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(3-(2,2-difluoroethoxy)-4-methylbenzyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-(2,2-difluoroethoxy)-3,5-dimethylbenzyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(3-(2,2-difluoroethoxy)-4-methylbenzyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-(difluoromethoxy)-3-methylbenzyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-(difluoromethoxy)-3-methylbenzyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(4-(difluoromethoxy)-3-methylbenzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-(difluoromethoxy)-3-methylbenzyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-(difluoromethoxy)-3-methylbenzyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-2-(4-(difluoromethoxy)-3-methylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-2-(4-(difluoromethoxy)-3-methylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide;     and -   2-(4-(difluoromethoxy)-3-methylbenzyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide;     or a prodrug thereof or a pharmaceutically acceptable salt thereof.

[8] More suitable individual compounds of the invention are:

-   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   2-hydroxy-2-methyl-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; -   N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)acetamide; -   N-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)acetamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; -   N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)pivalamide; -   N-ethyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-methoxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-propyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-(dimethylamino)ethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-hydroxy-2-methyl-N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; -   2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   2-hydroxy-2-methyl-N-(2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; -   N-isopropyl-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-N-(2,3-dihydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-methyl-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-cyanoethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-cyanoethyl)-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-ethyl-2-((5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-(2-hydroxyethoxy)ethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-N-(2,3-dihydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(4-hydroxybutyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-acetamidopropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-(methylsulfonamido)propyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-((2,2-difluoroethoxy)-3-methylbenzyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-((2,2-difluoroethoxy)-3-methylbenzyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide;     2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(3-hydroxypropyl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-N-(2-hydroxypropyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-N-(2-hydroxypropyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-N-(2,3-dihydroxypropyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-N-(2,3-dihydroxypropyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-N-(2-hydroxypropyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-N-(1-hydroxypropan-2-yl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-cyanoethyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-cyanoethyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((5-methyl-6-(2-(2,2,2-trifluoroethoxy)ethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-(2-(4-(trifluoromethyl)phenoxy)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(2-(4-(trifluoromethyl)phenoxy)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   2-(2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-cyclopropyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-cyclopropyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-cyclopropyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   N,6-dimethyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(3-methyl-4-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(3-methyl-4-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((6-(4-fluorophenoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-N-(3-(methylsulfonyl)propyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-((1-(2,2,2-trifluoroethoxy)isoquinolin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((1-(2,2,2-trifluoroethoxy)isoquinolin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((1-(2,2,2-trifluoroethoxy)isoquinolin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((1-(2,2,2-trifluoroethoxy)isoquinolin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((5-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-(methylsulfonyl)propyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((1-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-hydroxyethyl)-2-(3-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((5-(2,2,3,3,3-pentafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-ethyl-2-((5-(2,2,3,3,3-pentafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   N-(2-((5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   N-(2-acetamidoethyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-N-(2,3-dihydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(3-(trifluoromethyl)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-N-(2,3-dihydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-(4-(1,1,2,2-tetrafluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-((S)-2-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(1-hydroxypropan-2-yl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   2-hydroxy-2-methyl-N-(2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; -   N-methyl-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; -   2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-isopropyl-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-N-(1-hydroxypropan-2-yl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-hydroxy-2-methyl-N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; -   2-hydroxy-2-methyl-N-(2-(3-methyl-4-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; -   2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-hydroxy-2-methyl-N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; -   N-ethyl-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-methyl-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-ethyl-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; -   2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   N-(2-cyanoethyl)-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-((R)-2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-2-(4-(2,2-difluoroethoxy)-3,5-dimethylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-((R)-2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-((S)-2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (S)-2-(4-(2,2-difluoroethoxy)-3,5-dimethylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-((S)-2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   (R)-2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-(2,2-difluoroethoxy)-3,5-dimethylbenzyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-(2,2-difluoroethoxy)-3,5-dimethylbenzyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   2-(4-(difluoromethoxy)-3-methylbenzyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; -   and     2-(4-(difluoromethoxy)-3-methylbenzyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide;     or a prodrug thereof or a pharmaceutically acceptable salt thereof.

[9] The present invention provides a pharmaceutical composition comprising a compound or a prodrug thereof or a pharmaceutically acceptable salt thereof, as described in any one of [1] to [8], and a pharmaceutically acceptable carrier.

[10] The present invention provides the pharmaceutical composition as described in [9], further comprising another pharmacologically active agent.

[11] The present invention provides a method for the treatment of a condition or disorder in which TTX-S channel blockers are involved, in an animal, including a human, which comprises administering to the animal in need of such treatment a therapeutically effective amount of a compound or a prodrug thereof or a pharmaceutically acceptable salt thereof, as described in any one of [1] to [8].

[12] The present invention provides the method as described in [11], wherein said condition or disorder is selected from the group consisting of: pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain, multiple sclerosis, neurodegenerative disorder, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia, Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, breakthrough pain, postsurgical pain, stroke, cancer pain, seizure disorder and causalgia; and combinations thereof.

[13] The present invention provides a use of a compound described in any one of [1] to [8] or a pharmaceutically acceptable salt, prodrug, solvate or composition thereof for the manufacture of a medicament for the treatment of a condition or disorder in which TTX-S channel blockers are involved.

[14] The present invention provides the use as described in [13], wherein said condition or disorder is selected from the group consisting of: pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain, multiple sclerosis, neurodegenerative disorder, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia, Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, breakthrough pain, postsurgical pain, stroke, cancer pain, seizure disorder, causalgia, and chemo-induced pain;

and combinations thereof.

[15] The present invention provides a compound described in any one of [1] to [8] or a prodrug or a pharmaceutically acceptable salt for use in the treatment of a condition or disorder in which TTX-S channel blockers are involved.

[16] The present invention provides a process for preparing a pharmaceutical composition comprising mixing a compound described in any one of [1] to [8] or a prodrug thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

Advantageous Effects of Invention

The pyrazolopyridine derivatives of the present invention are sodium channel blockers and have a number of therapeutic applications, particularly in the treatment of pain.

More particularly, the pyrazolopyridine derivatives of the invention are selective tetrodotoxin-sensitive (TTX-S) blockers. In the discussion that follows, the invention is exemplified by reference to the inhibition of Na_(V1.3) or Na_(V1.7) channel as the TTX-S channels.

They show the affinity for Na_(V1.3) or Na_(V1.7) channel which is significantly greater than their affinity for Na_(V1.5) channel as the tetrodotoxin-resistant (TTX-R) sodium channels.

The pyrazolopyridine derivatives of the invention show good selectivity for the Na_(V1.3) or Na_(V1.7) channel as compared with Na_(V1.5) channel.

In particular, the pyrazolopyridine derivatives of the present invention are selective for the TTX-S channels over the Na_(V1.5) channel, leading to improvements in the side-effect profile.

The pyrazolopyridine derivatives of the present invention are therefore useful in the treatment of a wide range of disorders, particularly pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain including post-surgical pain, and mixed pain types involving the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spine, urogenital system, cardiovascular system and CNS, including cancer pain, back pain, orofacial pain and chemo-induced pain.

Other conditions that may be treated with the pyrazolopyridine derivatives of the present invention include multiple sclerosis, neurodegenerative disorders, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, breakthrough pain, postsurgical pain, stroke, cancer pain, seizure disorder and causalgia.

DESCRIPTION OF EMBODIMENTS

Examples of conditions or disorders mediated by TTX-S channels include, but are not limited to, TTX-S channels related diseases. The compounds of the present invention show the TTX-S channels blocking activity. The compounds of the present invention may show less toxicity, good absorption and distribution, good solubility, less protein binding affinity other than TTX-S channels, less drug-drug interaction, good metabolic stability, reduced inhibitory activity at HERG channel, and/or reduced QT prolongation.

As appreciated by those of skill in the art, “halogen” or “halo” as used herein is intended to include fluoro, chloro, bromo and iodo. Similarly, 1-6, as in C₁₋₆ is defined to identify the number as having 1, 2, 3, 4, 5 or 6. According to the definition, for example, C₁₋₆, as in C₁₋₆ alkyl is defined to identify the alkyl group as having 1, 2, 3, 4, 5 or 6 carbons. Similarly, C₂₋₆ alkenyl is defined to identify the alkenyl group as having 2, 3, 4, 5 or 6 carbons. A group which is designated as being independently substituted with substituents may be independently substituted with multiple numbers of such substituents.

The term “alkyl”, as used herein, means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like.

The term “alkoxy”, as used herein, means an —O-alkyl such as, but not limited to, methoxy, ethoxy, propoxy, or 2-propoxy, butoxy (including all isomeric forms), and the like.

The term “alkylthio”, as used herein, means a —S-alkyl such as, but not limited to, methylthio, ethylthio, and the like.

The term “alkylamino”, as used herein, means a —NH-alkyl such as, but not limited to, methylamino, ethylamino, propylamino, 2-propylamino, and the like.

The term “alkenyl”, as used herein, means a hydrocarbon radical having at least one double bond, which may be in a E- or a Z-arrangement, including, but not limited to, ethenyl, propenyl, 1-butenyl, 2-butenyl and the like.

The term “cycloalkyl”, as used herein, means a mono- or bicyclic ring such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norboranyl, adamantyl groups, and the like.

The term “alkylene”, as used herein, means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated, e.g., but not limited to, methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

The term “cycloalkylene”, as used herein, means a mono- or bicyclic ring such as, but not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, and the like.

The term “aryl”, as used herein, means mono- or bi-carbocyclic or mono- or bi-heterocyclic ring which may contain 0-4 heteroatoms selected from O, N and S such as, but not limited to, phenyl, naphthyl, benzofuranyl, benzofurazanyl, benzimidazolonyl, benzoimidazolyl, benzoisothiazolyl, benzoisoxazolyl, benzothiadiazolyl, benzothiazolyl, benzoxadiazolyl, benzoxazolonyl, benzoxazolyl, benzothiophenyl, benzotriazolyl, carbazolyl, carbolinyl, chromanyl, cinnolinyl, 2,3-dioxoindolyl, furanyl, furazanyl, furopyridyl, furopyrrolyl, imidazolyl, imidazopyrazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazothiazolyl, indazolyl, indolazinyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolyl, isoquinolyl, isoxazolopyridyl, isoxazolinyl, isoxazolyl, isothiazolyl, naphthyridinyl, oxazolinyl, oxadiazolyl, oxazolyl, oxetanyl, 2-oxoindolyl, phthalazyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrazolyl, pyrazinyl, pyridyl, pyrimidyl, pyridazinyl, pyridopyrimidinyl, pyrrolopyridyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolopyridyl, tetrazolyl, thiadiazolyl, thiazolyl, thiophenyl, thienopyrazinyl, thienopyrazolyl, thienopyridyl, thienopyrrolyl, triazolopyrimidinyl, triazolyl, 4-oxo-1,4-dihydroquinolyl, 2-oxo-1,2-dihydropyridyl, 4-oxo-1,4-dihydropyrimidyl, 2-oxo-1,2-dihydroquinolyl, 4-oxo-4H-pyrido[1,2-a]pyrimidyl, 4-oxo-1,4-dihydro-1,8-naphthyridyl, and N-oxides thereof.

The term “heterocyclyl” as used herein includes both unsaturated and saturated heterocyclic moieties, wherein the unsaturated heterocyclic moieties (i.e. “heteroaryl”) include, but not limited to, benzofuranyl, benzofurazanyl, benzimidazolonyl, benzoimidazolyl, benzoisothiazolyl, benzoisoxazolyl, benzothiadiazolyl, benzothiazolyl, benzoxadiazolyl, benzoxazolonyl, benzoxazolyl, benzothiophenyl, benzotriazolyl, carbazolyl, carbolinyl, chromanyl, cinnolinyl, 2,3-dioxoindolyl, furanyl, furazanyl, furopyridyl, furopyrrolyl, imidazolyl, imidazopyrazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazothiazolyl, indazolyl, indolazinyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolyl, isoquinolyl, isoxazolopyridyl, isoxazolinyl, isoxazolyl, isothiazolyl, naphthyridinyl, oxazolinyl, oxadiazolyl, oxazolyl, oxetanyl, 2-oxoindolyl, oxoisoindolyl, phthalazyl, pyrazolyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrazinyl, pyridyl, pyrimidyl, pyridazinyl, pyridopyrimidinyl, pyrrolopyridyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolopyridyl, tetrazolyl, thiadiazolyl, thiazolyl, thiophenyl, thienopyrazinyl, thienopyrazolyl, thienopyridyl, thienopyrrolyl, triazolopyrimidinyl, triazolyl, 4-oxo-1,4-dihydroquinolyl, 2-oxo-1,2-dihydropyridyl, 4-oxo-1,4-dihydropyrimidyl, 2-oxo-1,2-dihydroquinolyl, 4-oxo-4H-pyrido[1,2-a]pyrimidyl, 4-oxo-1,4-dihydro-1,8-naphthyridyl, and N-oxides thereof, and wherein the saturated heterocyclic moieties include, but not limited to, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, triazolopyrimidyl, tetrahydrothienyl, pyrrolidinonyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 2-oxo-2,5,6,7-tetrahydro-1H-cyclopentapyridyl, 4,5,6,7-tetrahydro-indazolyl, 5,6,7,8-tetrahydro-1,6-naphthyridyl, and N-oxides thereof and S-oxides thereof.

The term “C₀”, as used herein, means direct bond.

The term “protecting group”, as used herein, means a hydroxy or amino protecting group which is selected from typical hydroxy or amino protecting groups described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 2007).

The terms “treating” or “treatment”, as used herein, includes prohibiting, restraining, slowing, stopping, or reversing the progression or severity of an existing symptom or disorder. As used herein, the term “preventing” or “to prevent” includes prohibiting, restraining, or inhibiting the incidence or occurrence of a symptom or disorder”.

As used herein, the article “a” or “an” refers to both the singular and plural form of the object to which it refers unless indicated otherwise.

Included within the scope of the “compounds of the invention” are all salts, solvates, hydrates, complexes, polymorphs, prodrugs, radiolabeled derivatives, stereoisomers and optical isomers of the compounds of formula (I).

Compounds of formula (I) can form acid addition salts thereof. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci, 1977, 66, 1-19, such as acid addition salts formed with inorganic acids e.g., but not limited to, hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e.g., but not limited to, succinic, maleic, formic, acetic, trifluoroacetic, propionic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms. In addition, certain compounds containing an acidic function such as a carboxy can be isolated in the form of their inorganic salt in which the counter ion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases such as choline, arginine, benzathine, diethylamine, glycine, lysine, meglumine, olamine, 2-amino-2-methylpropan-1-ol, benethamine, tert-butylamine, epolamine, ethylenediamine, hydrabamine, morpholine, piperazine, procaine, triethanolamine, diethanolamine, monoethanolamine, triisopropanolamine, and tromethamine.

Also within the scope of the invention are so-called “prodrugs” of the compounds of formula (I). Thus certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as “prodrugs”. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).

The term “animal,” as used herein, includes a mammalian subject or a non-mammalian subject. Examples of suitable mammalian subject may include, without limit, human, rodents, companion animals, livestock, and primates. Suitable rodents may include, but are not limited to, mice, rats, hamsters, gerbils, and guinea pigs. Suitable companion animals may include, but are not limited to, cats, dogs, rabbits, and ferrets. Suitable livestock may include, but are not limited to, horses, goats, sheep, swine, cattle, llamas, and alpacas. Suitable primates may include, but are not limited to, chimpanzees, lemurs, macaques, marmosets, spider monkeys, squirrel monkeys, and vervet monkeys. Examples of suitable non-mammalian subject may include, without limit, birds, reptiles, amphibians, and fish. Non-limiting examples of birds include chickens, turkeys, ducks, and geese. The preferred mammalian subject is a human.

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as ‘pro-moieties’ as described, for example, in Design of Prodrugs by H Bundgaard (Elsevier, 1985). Some examples of prodrugs in accordance with the invention include:

(i) where the compound of formula (I) contains an alcohol functionality (—OH), compounds wherein the hydroxy group is replaced with a moiety convertible in vivo into the hydroxy group. Said moiety convertible in vivo into the hydroxy group means a moiety transformable in vivo into a hydroxyl group by e.g. hydrolysis and/or by an enzyme, e.g. an esterase. Examples of said moiety include, but are not limited to, ester and ether groups which may be hydrolyzed easily in vivo. Preferred are the moieties replaced the hydrogen of hydroxy group with acyloxyalkyl, 1-(alkoxycarbonyloxy)alkyl, phthalidyl and acyloxyalkyloxycarbonyl such as pivaloyloxymethyloxycarbonyl; and

(ii) where the compound of the formula (I) contains an amino group, a pyrazolopyridine derivative prepared by reacting with a suitable acid halide or a suitable acid anhydride is exemplified as a prodrug. A particularly preferred pyrazolopyridine derivative as a prodrug is —NHCO(CH₂)₂OCH₃, —NHCOCH(NH₂)CH₃ or the like.

Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.

Compounds of formula (I) and salts thereof may be prepared in crystalline or noncrystalline form, and, if crystalline, may optionally be hydrated or solvated. This invention includes within its scope stoichiometric hydrates or solvates as well as compounds containing variable amounts of water and/or solvent.

Salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts.

Compounds of formula (I) may have polymorphs in crystalline form, which are within the scope of the present invention.

Additionally, compounds of formula (I) may be administered as prodrugs. As used herein, a “prodrug” of a compound of formula (I) is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of formula (I) in vivo. Administration of a compound of formula (I) as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of action of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome a side effect or other difficulty encountered with the compound. Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.

In certain of the compounds of formula (I), there may be one or more chiral carbon atoms. In such cases, compounds of formula (I) exist as stereoisomers. The invention extends to all optical isomers such as stereoisomeric forms of the compounds of formula (I) including enantiomers, diastereoisomers and mixtures thereof, such as racemates. The different stereoisomeric forms may be separated or resolved one from the other by conventional methods or any given isomer may be obtained by conventional stereoselective or asymmetric syntheses.

Certain of the compounds herein can exist in various tautomeric forms and it is to be understood that the invention encompasses all such tautomeric forms.

The invention also includes isotopically-labeled compounds, which are identical to those described herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁸F, ¹²³I and ¹²⁵I. Compounds of the invention that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as ³H, ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. ¹¹C and ¹⁸F isotopes are particularly useful in PET (positron emission tomography), and ¹²³I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, then substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

With respect to other compounds disclosed in the art, certain compounds exhibit unexpected properties, such as with respect to duration of action and/or metabolism, such as increased metabolic stability, enhanced oral bioavailability or absorption, and/or decreased drug-drug interactions.

The compounds of formula (I), being Na_(V1.3) and/or Na_(V1.7) channel blockers, are potentially useful in the treatment of a range of disorders. The treatment of pain, particularly chronic, inflammatory, neuropathic, nociceptive and visceral pain, is a preferred use.

Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment. The system operates through a specific set of primary sensory neurones and is activated by noxious stimuli via peripheral transducing mechanisms (see Millan, 1999, Prog. Neurobiol., 57, 1-164 for a review). These sensory fibres are known as nociceptors and are characteristically small diameter axons with slow conduction velocities. Nociceptors encode the intensity, duration and quality of noxious stimulus and by virtue of their topographically organised projection to the spinal cord, the location of the stimulus. The nociceptors are found on nociceptive nerve fibres of which there are two main types, A-delta fibres (myelinated) and C fibres (non-myelinated). The activity generated by nociceptor input is transferred, after complex processing in the dorsal horn, either directly, or via brain stem relay nuclei, to the ventrobasal thalamus and then on to the cortex, where the sensation of pain is generated.

Pain may generally be classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually in twelve weeks or less). It is usually associated with a specific cause such as a specific injury and is often sharp and severe. It is the kind of pain that can occur after specific injuries resulting from surgery, dental work, a strain or a sprain. Acute pain does not generally result in any persistent psychological response. In contrast, chronic pain is long-term pain, typically persisting for more than three months and leading to significant psychological and emotional problems. Common examples of chronic pain are neuropathic pain (e.g. painful diabetic neuropathy, postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain and chronic post-surgical pain.

When a substantial injury occurs to body tissue, via disease or trauma, the characteristics of nociceptor activation are altered and there is sensitisation in the periphery, locally around the injury and centrally where the nociceptors terminate. These effects lead to a hightened sensation of pain. In acute pain these mechanisms can be useful, in promoting protective behaviours which may better enable repair processes to take place. The normal expectation would be that sensitivity returns to normal once the injury has healed. However, in many chronic pain states, the hypersensitivity far outlasts the healing process and is often due to nervous system injury. This injury often leads to abnormalities in sensory nerve fibres associated with maladaptation and aberrant activity (Woolf & Salter, 2000, Science, 288, 1765-1768).

Clinical pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms. Patients tend to be quite heterogeneous and may present with various pain symptoms. Such symptoms include: 1) spontaneous pain which may be dull, burning, or stabbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); and 3) pain produced by normally innocuous stimuli (allodynia—Meyer et al., 1994, Textbook of Pain, 13-44). Although patients suffering from various forms of acute and chronic pain may have similar symptoms, the underlying mechanisms may be different and may, therefore, require different treatment strategies. Pain can also therefore be divided into a number of different subtypes according to differing pathophysiology, including nociceptive, inflammatory and neuropathic pain.

Nociceptive pain is induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where pain is perceived (Meyer et al., 1994, Textbook of Pain, 13-44). The activation of nociceptors activates two types of afferent nerve fibres. Myelinated A-delta fibres transmit rapidly and are responsible for sharp and stabbing pain sensations, whilst unmyelinated C fibres transmit at a slower rate and convey a dull or aching pain. Moderate to severe acute nociceptive pain is a prominent feature of pain from central nervous system trauma, strainssprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, cancer pain and back pain. Cancer pain may be chronic pain such as tumour related pain (e.g. bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (e.g. postchemotherapy syndrome, chronic postsurgical pain syndrome or post radiation syndrome). Cancer pain may also occur in response to chemotherapy, immunotherapy, hormonal therapy or radiotherapy. Back pain may be due to herniated or ruptured intervertebral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament. Back pain may resolve naturally but in some patients, where it lasts over 12 weeks, it becomes a chronic condition which can be particularly debilitating.

Neuropathic pain is currently defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. Nerve damage can be caused by trauma and disease and thus the term ‘neuropathic pain’ encompasses many disorders with diverse aetiologies. These include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central poststroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic pain is pathological as it has no protective role. It is often present well after the original cause has dissipated, commonly lasting for years, significantly decreasing a patient's quality of life (Woolf and Mannion, 1999, Lancet, 353, 1959-1964). The symptoms of neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6, S141-S147; Woolf and Mannion, 1999, Lancet, 353, 1959-1964). They include spontaneous pain, which can be continuous, and paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).

The inflammatory process is a complex series of biochemical and cellular events, activated in response to tissue injury or the presence of foreign substances, which results in swelling and pain (Levine and Taiwo, 1994, Textbook of Pain, 45-56). Arthritic pain is the most common inflammatory pain. Rheumatoid disease is one of the commonest chronic inflammatory conditions in developed countries and rheumatoid arthritis is a common cause of disability. The exact aetiology of rheumatoid arthritis is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson, 1994, Textbook of Pain, 397-407). It has been estimated that almost 16 million Americans have symptomatic osteoarthritis (OA) or degenerative joint disease, most of whom are over 60 years of age, and this is expected to increase to 40 million as the age of the population increases, making this a public health problem of enormous magnitude (Houge & Mersfelder, 2002, Ann Pharmacother., 36, 679-686; McCarthy et al., 1994, Textbook of Pain, 387-395). Most patients with osteoarthritis seek medical attention because of the associated pain. Arthritis has a significant impact on psychosocial and physical function and is known to be the leading cause of disability in later life. Ankylosing spondylitis is also a rheumatic disease that causes arthritis of the spine and sacroiliac joints. It varies from intermittent episodes of back pain that occur throughout life to a severe chronic disease that attacks the spine, peripheral joints and other body organs.

Another type of inflammatory pain is visceral pain which includes pain associated with inflammatory bowel disease (IBD). Visceral pain is pain associated with the viscera, which encompass the organs of the abdominal cavity. These organs include the sex organs, spleen and part of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non-digestive visceral pain. Commonly encountered gastrointestinal (GI) disorders that cause pain include functional bowel disorder (FBD) and inflammatory bowel disease (IBD). These GI disorders include a wide range of disease states that are currently only moderately controlled, including, in respect of FBD, gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and, in respect of IBD, Crohn's disease, ileitis and ulcerative colitis, all of which regularly produce visceral pain. Other types of visceral pain include the pain associated with dysmenorrhea, cystitis and pancreatitis and pelvic pain.

It should be noted that some types of pain have multiple aetiologies and thus can be classified in more than one area, e.g. back pain and cancer pain have both nociceptive and neuropathic components.

Other types of pain include:

(i) pain resulting from musculo-skeletal disorders, including myalgia, fibromyalgia, spondylitis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis and pyomyositis;

(ii) heart and vascular pain, including pain caused by angina, myocardical infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma and skeletal muscle ischemia;

(iii) head pain, such as migraine (including migraine with aura and migraine without aura), cluster headache, tension-type headache mixed headache and headache associated with vascular disorders; and

(vi) orofacial pain, including dental pain, otic pain, burning mouth syndrome and temporomandibular myofascial pain.

Compounds of formula (I) are also expected to be useful in the treatment of multiple sclerosis.

The invention also relates to therapeutic use of compounds of formula (I) as agents for treating or relieving the symptoms of neurodegenerative disorders. Such neurodegenerative disorders include, for example, Alzheimer's disease, Huntington's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. The present invention also covers treating neurodegenerative disorders termed acute brain injury. These include but are not limited to: stroke, head trauma, and asphyxia. Stroke refers to a cerebral vascular disease and may also be referred to as a cerebral vascular accident (CVA) and includes acute thromboembolic stroke. Stroke includes both focal and global ischemia. Also, included are transient cerebral ischemic attacks and other cerebral vascular problems accompanied by cerebral ischemia. These vascular disorders may occur in a patient undergoing carotid endarterectomy specifically or other cerebrovascular or vascular surgical procedures in general, or diagnostic vascular procedures including cerebral angiography and the like. Other incidents are head trauma, spinal cord trauma, or injury from general anoxia, hypoxia, hypoglycemia, hypotension as well as similar injuries seen during procedures from embole, hyperfusion, and hypoxia. The instant invention would be useful in a range of incidents, for example, during cardiac bypass surgery, in incidents of intracranial hemorrhage, in perinatal asphyxia, in cardiac arrest, and status epilepticus.

A skilled physician will be able to determine the appropriate situation in which subjects are susceptible to or at risk of, for example, stroke as well as suffering from stroke for administration by methods of the present invention.

TTX-S sodium channels have been implicated in a wide range of biological functions. This has suggested a potential role for these receptors in a variety of disease processes in humans or other species. The compounds of the present invention have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of neurological and psychiatric disorders associated with TTX-S sodium channels, including one or more of the following conditions or diseases: pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain, multiple sclerosis, neurodegenerative disorder, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, breakthrough pain, postsurgical pain, stroke, cancer pain, seizure disorder, causalgia, and chemo-induced pain.

The dosage of active ingredient in the compositions of this invention may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The active ingredient may be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy.

The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. The dose will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets then being followed by a patient, concurrent medication, and other factors which those skilled in the art will recognize.

For administration to human patients, the total daily dose of the compounds of the invention is typically in the range 0.1 mg to 1000 mg depending, of course, on the mode of administration. For example, oral administration may require a total daily dose of from 1 mg to 1000 mg, while an intravenous dose may only require from 0.1 mg to 100 mg. The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.

These dosages are based on an average human subject having a weight of about 60 kg to 70 kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.

In one embodiment, the dosage range will be about 0.5 mg to 500 mg per patient per day; in another embodiment about 0.5 mg to 200 mg per patient per day; in another embodiment about 1 mg to 100 mg per patient per day; and in another embodiment about 5 mg to 50 mg per patient per day; in yet another embodiment about 1 mg to 30 mg per patient per day. Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation such as comprising about 0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mg active ingredient. The pharmaceutical composition may be provided in a solid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg or 250 mg active ingredient. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, such as once or twice per day.

Compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of the present invention or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention is envisioned. However, the combination therapy may also include therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly.

Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention. The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.

Likewise, compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is envisioned. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.

The weight ratio of the compound of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, including about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).

A TTX-S sodium channels blocker may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of inflammatory, pain and urological diseases or disorders. For example, a TTX-S sodium channels blocker, particularly a compound of formula (I), or a prodrug thereof or a pharmaceutically acceptable salt or solvate thereof, as defined above, may be administered simultaneously, sequentially or separately in combination with one or more agents selected from

-   -   an opioid analgesic, e.g. morphine, heroin, hydromorphone,         oxymorphone, levorphanol, levallorphan, methadone, meperidine,         fentanyl, cocaine, codeine, dihydrocodeine, oxycodone,         hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone,         naltrexone, buprenorphine, butorphanol, nalbuphine or         pentazocine;     -   a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin,         diclofenac, diflusinal, etodolac, fenbufen, fenoprofen,         flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen,         ketorolac, meclofenamic acid, mefenamic acid, meloxicam,         nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine,         oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac,         tolmetin or zomepirac;     -   a barbiturate sedative, e.g. amobarbital, aprobarbital,         butabarbital, butabital, mephobarbital, metharbital,         methohexital, pentobarbital, phenobartital, secobarbital,         talbutal, theamylal or thiopental;     -   a benzodiazepine having a sedative action, e.g.         chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam,         oxazepam, temazepam or triazolam;     -   an H1 antagonist having a sedative action, e.g. diphenhydramine,         pyrilamine, promethazine, chlorpheniramine or chlorcyclizine; —a         sedative such as glutethimide, meprobamate, methaqualone or         dichloralphenazone;     -   a skeletal muscle relaxant, e.g. baclofen, carisoprodol,         chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;     -   an NMDA receptor antagonist, e.g. dextromethorphan         ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan         ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine,         pyrroloquinoline quinine,         cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine,         EN-3231 (MorphiDex™, a combination formulation of morphine and         dextromethorphan), topiramate, neramexane or perzinfotel         including an NR2B antagonist, e.g. ifenprodil, traxoprodil or         (−)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;     -   an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine,         guanfacine, dexmedetomidine, modafinil, or         4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)         quinazoline;     -   a tricyclic antidepressant, e.g. desipramine, imipramine,         amitriptyline or nortriptyline;     -   an anticonvulsant, e.g. carbamazepine, lamotrigine, topiratmate         or valproate;     -   a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1         antagonist, e.g.         alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione         (TAK-637),         5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one         (MK-869), aprepitant, lanepitant, dapitant or         3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine         (2S,3S);     -   a muscarinic antagonist, e.g. oxybutynin, tolterodine,         propiverine, trospium chloride, darifenacin, solifenacin,         temiverine and ipratropium;     -   a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib,         parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;     -   a coal-tar analgesic, in particular paracetamol;     -   a neuroleptic such as droperidol, chlorpromazine, haloperidol,         perphenazine, thioridazine, mesoridazine, trifluoperazine,         fluphenazine, clozapine, olanzapine, risperidone, ziprasidone,         quetiapine, sertindole, aripiprazole, sonepiprazole,         blonanserin, iloperidone, perospirone, raclopride, zotepine,         bifeprunox, asenapine, lurasidone, amisulpride, balaperidone,         palindore, eplivanserin, osanetant, rimonabant, meclinertant,         Miraxion™ or sarizotan;     -   a vanilloid receptor agonist (e.g. resiniferatoxin) or         antagonist (e.g. capsazepine);     -   a transient receptor potential cation channel subtype (V1, V2,         V3, V4, M8, M2, A1) agonist or antagonist;     -   a beta-adrenergic such as propranolol;     -   a local anaesthetic such as mexiletine;     -   a corticosteroid such as dexamethasone;     -   a 5-HT receptor agonist or antagonist, particularly a 5-HT1B1D         agonist such as eletriptan, sumatriptan, naratriptan,         zolmitriptan or rizatriptan;     -   a 5-HT2A receptor antagonist such as         R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol         (MDL-100907);     -   a cholinergic (nicotinic) analgesic, such as ispronicline         (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine         (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine         (ABT-594) or nicotine;     -   Tramadol™;     -   a PDEV inhibitor, such as         5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one         (sildenafil),         (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione         (IC-351 or tadalafil),         2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one         (vardenafil),         5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,         5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,         5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,         4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide,         3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;     -   an alpha-2-delta ligand such as gabapentin, pregabalin,         3-methylgabapentin,         (3-(aminomethyl)bicyclo[3.2.0]hept-3-yl)acetic acid,         (3S,5R)-3-(aminomethyl)-5-methylheptanoic acid,         (3S,5R)-3-amino-5-methylheptanoic acid,         (3S,5R)-3-amino-5-methyloctanoic acid,         (2S,4S)-4-(3-chlorophenoxy)proline,         (2S,4S)-4-(3-fluorobenzyl)proline,         [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,         3-((1-(aminomethyl)cyclohexyl)methyl)-4H-[1,2,4]oxadiazol-5-one,         C-[1-((1H-tetrazol-5-yl)methyl)cycloheptyl]methylamine,         (3S,4S)-(1-(aminomethyl)-3,4-dimethylcyclopentyl)acetic acid,         (3S,5R)-3-(aminomethyl)-5-methyloctanoic acid,         (3S,5R)-3-amino-5-methylnonanoic acid,         (3S,5R)-3-amino-5-methyloctanoic acid,         (3R,4R,5R)-3-amino-4,5-dimethylheptanoic acid, and         (3R,4R,5R)-3-amino-4,5-dimethyloctanoic acid;     -   a cannabinoid;     -   a metabotropic glutamate subtype 1 receptor (mGluR1) antagonist;     -   a serotonin reuptake inhibitor such as sertraline, sertraline         metabolite demethylsertraline, fluoxetine, norfluoxetine         (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine,         citalopram, citalopram metabolite desmethylcitalopram,         escitalopram, d,l-fenfluramine, femoxetine, ifoxetine,         cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine         and trazodone;     -   a noradrenaline (norepinephrine) reuptake inhibitor, such as         maprotiline, lofepramine, mirtazapine, oxaprotiline, fezolamine,         tomoxetine, mianserin, buproprion, buproprion metabolite         hydroxybuproprion, nomifensine and viloxazine (Vivalan™)         especially a selective noradrenaline reuptake inhibitor such as         reboxetine, in particular (S,S)-reboxetine;     -   a dual serotonin-noradrenaline reuptake inhibitor, such as         venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine,         clomipramine, clomipramine metabolite desmethylclomipramine,         duloxetine, milnacipran and imipramine;     -   an inducible nitric oxide synthase (iNOS) inhibitor such as         S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine,         S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine,         S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine,         (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic         acid,         2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-5-chloro-3-pyridinecarbonitrile;         2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile,         (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol,         2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile,         2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile,         N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine,         or guanidinoethyldisulfide;     -   an acetylcholinesterase inhibitor such as donepezil;     -   a prostaglandin E2 subtype 4 (EP4) antagonist such as         N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide         or         4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic         acid;     -   a leukotriene B4 antagonist; such as         1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic         acid (CP-105696),         5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric         acid (ONO-4057) or DPC-11870,     -   a 5-lipoxygenase inhibitor, such as zileuton,         6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone         (ZD-2138), or         2,3,5-trimethyl-6-(3-pyridylmethyl),1,4-benzoquinone (CV-6504);     -   a sodium channel blocker, such as lidocaine;     -   a calcium channel blocker, such as ziconotide, zonisamide,         mibefradil;     -   a 5-HT3 antagonist, such as ondansetron;     -   a chemotherapy drug such as oxaliplatin, 5-fluorouracil,         leukovolin, paclitaxel;     -   a calcitonin gene related peptide (CGRP) antagonist;     -   a bradykinin (BK1 and BK2) antagonist;     -   a voltage gated sodium dependent channel blocker (Na_(V1.3),         Na_(V1.7), Na_(V1.8));     -   a voltage dependent calcium channel blocker (N-type, T-type);     -   a P2X (ion channel type ATP receptor) antagonist;     -   an acid-sensing ion channel (ASIC1a, ASIC3) antagonist;     -   an Angiotensin AT2 antagonist;     -   a Chemokine CCR2B receptor antagonist;     -   a Cathepsin (B, S, K) inhibitor;     -   a sigma1 receptor agonist or antagonist;

and the pharmaceutically acceptable salts and solvates thereof.

Such combinations offer significant advantages, including synergistic activity, in therapy.

A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrate compositions are generally preferred. Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); tabletting lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); and acceptable wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated according to methods well known in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non-aqueous vehicles (which may include edible oils e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid), and, if desired, conventional flavourings or colorants, buffer salts and sweetening agents as appropriate. Preparations for oral administration may be suitably formulated to give controlled release of the active compound or pharmaceutically acceptable salt thereof.

For parenteral administration, fluid unit dosage forms are prepared utilising a compound of formula (I) or pharmaceutically acceptable salt thereof and a sterile vehicle. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose, utilising a compound of formula (I) or pharmaceutically acceptable salt thereof and a sterile vehicle, optionally with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, stabilising agents, solubilising agents or suspending agents. They may also contain a preservative.

Compounds of formula (I) or pharmaceutically acceptable salts thereof may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

Compounds of formula (I) or pharmaceutically acceptable salts may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of formula (I) or pharmaceutically acceptable salts may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

For intranasal administration, compounds formula (I) or pharmaceutically acceptable salts thereof may be formulated as solutions for administration via a suitable metered or unitary dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device. Thus compounds of formula (I) or pharmaceutically acceptable salts thereof may be formulated for oral, buccal, parenteral, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose). The compounds of formula (I) and pharmaceutically acceptable salts thereof may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Ointments for administration to the eye may be manufactured in a sterile manner using sterilized components.

General Synthesis

Throughout the instant application, the following abbreviations are used with the following meanings:

DCM Dichloromethane

DMF N,N-Dimethylformamide

DMA N,N-Dimethylacetamide

DME 1,2-DimethoxyethaneDMSO Dimethyl sulfoxide

EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride

e.e. Enantiomeric Excess

ESI Electrospray Ionization

EtOAc Ethyl acetate

EtOH Ethanol

HOBT 1-Hydroxybenztriazole

HBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium Hexafluorophosphate

HPLC High-Performance Liquid Chromatography

LC Liquid Chromatography

LG Leaving Group

tR Retention Time

MeCN Acetonitrile

MeOH Methanol

MHz Megahertz

MS Mass Spectrometry

NMR Nuclear Magnetic Resonance

PG Protecting Group

rt Room Temperature

TFA Trifluoroacetic Acid

THF Tetrahydrofuran

TLC Thin Layer Chromatography

UV Ultraviolet

The term of “base” is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here. Examples of such bases include, but not limited to: alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium phosphate, and barium hydroxide; alkali metal hydrides, such as lithium hydride, sodium hydride, and potassium hydride; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, and potassium t-butoxide; alkali metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; alkali metal hydrogencarbonates, such as lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), lutidine, and colidine; alkali metal amides, such as lithium amide, sodium amide, potassium amide, lithium diisopropyl amide, potassium diisopropyl amide, sodium diisopropyl amide, lithium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide. Of these, triethylamine, diisopropylethylamine, DBU, DBN, DABCO, pyridine, lutidine, colidine, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, potassium carbonate, potassium hydrogencarbonate, potassium hydroxide, potassium phosphate, barium hydroxide, and cesium carbonate are preferred.

The reactions are normally and preferably effected in the presence of inert solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include, but not limited to: halogenated hydrocarbons, such as DCM, chloroform, carbon tetrachloride, and dichloroethane; ethers, such as diethyl ether, diisopropyl ether, THF, and dioxane; aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; amides, such as, DMF, DMA, and hexamethylphosphoric triamide; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, N,N-dimethylaniline, and N,N-diethylaniline; alcohols, such as methanol, ethanol, propanol, isopropanol, and butanol; nitriles, such as acetonitrile and benzonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO) and sulfolane; ketones, such as acetone and diethylketone. Of these solvents, including but not limited to DMF, DMA, DMSO, THF, diethylether, diisopropylether, dimethoxyethane, acetonitrile, DCM, dichloroethane and chloroform are preferred.

EXAMPLES

The invention is illustrated in the following non-limiting examples in which, unless stated otherwise: all reagents are commercially available, all operations are carried out at room or ambient temperature, that is, in the range of about 18-25° C.; evaporation of solvent is carried out using a rotary evaporator under reduced pressure with a bath temperature of up to about 60° C.; reactions are monitored by thin layer chromatography (TLC) and reaction times are given for illustration only; the structure and purity of all isolated compounds are assured by at least one of the following techniques: TLC (Merck silica gel 60 F₂₅₄ precoated TLC plates or Merck NH₂ F₂₅₄ precoated HPTLC plates), mass spectrometry or NMR. Yields are given for illustrative purposes only. Flash column chromatography is carried out using Merck silica gel 60 (230-400 mesh ASTM), Fuji Silysia Chromatorex (registered trade mark) DU3050 (Amino Type), Wako Wakogel C300-HG, Biotage silica KP-Sil, Yamazen Hi-FLASH column, YMC DispoPack-SIL, or Biotage amino bounded silica KP-NH. The purification of compounds using HPLC (preparative LC-MS) is performed by the following apparatus and conditions.

Apparatus; Waters MS-trigger AutoPurification(trademark) system

Column; Waters XTerra C18, 19×50 mm, 5 micrometer particle

Condition A: Methanol or acetonitrile/0.01%(vv) ammonia aqueous solution

Condition B: Methanol or acetonitrile/0.05%(vv) formic acid aqueous solution

Low-resolution mass spectral data (ESI) are obtained by the following apparatus and conditions: Apparatus; Waters Alliance HPLC system on ZQ or ZMD mass spectrometer and UV detector. NMR data are determined at 270 MHz (JEOL JNM-LA 270 spectrometer) or 300 MHz (JEOL JNM-LA300) using deuterated chloroform (99.8% D) or dimethylsulfoxide (99.9% D) as solvent unless indicated otherwise, relative to tetramethylsilane (TMS) as internal standard in parts per million (ppm); conventional abbreviations used are: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad, etc. Chemical symbols have their usual meanings; M (mol(s) per liter), L(liter(s)), mL (milliliter(s)), g (gram(s)), mg(milligram(s)), mol (moles), mmol (millimoles).

Each prepared compound is generally named by ChemBioDraw (Ultra, version 12.0, CambridgeSoft).

Conditions for determining HPLC retention time:

Method: QC1

Apparatus: Waters ACQUITY Ultra Parformance LC with TUV Detector and ZQ mass spectrometer

Column: Waters ACQUITY C18, 2.1×100 mm, 1.7 micrometer particle size

Column Temperature: 60° C.

Flow rate: 0.7 mL/min

Run time: 3 min

UV detection: 210 nm

MS detection: ESI positive/negative mode

Mobile phases:

A1: 10 mM Ammonium acetate

B1: acetonitrile

Gradient program: (QC_neutral_full_3 min)

TABLE 1 Time (min) A1 (%) B1 (%) 0 95 5 0.1 95 5 1.8 5 95 2.3 95 5

Method: QC2

Apparatus: Waters 2795 Alliance HPLC with ZQ2000 mass spectrometer and 2996 PDA Detector

Column: XBridge C18, 2.1×50 mm, 3.5 micrometer particle size

Column Temperature: 45° C.

Flow rate: 1.2 mL/min

Run time: 4.5 min

UV detection: 210-400 nm scan

MS detection: ESI positive/negative mode

Mobile phases:

A: Water

B: MeCN

C: 1% aqueous HCOOH solution

D: 1% aqueous NH₃ solution

Gradient Program:

TABLE 2 Time (min) A (%) B (%) C (%) D (%) 0 85 10 2.5 2.5 0.2 85 10 2.5 2.5 3.2 0 95 2.5 2.5 3.7 0 95 2.5 2.5 3.71 85 10 2.5 2.5 4.5 85 10 2.5 2.5

All of the pyrazolopyridine derivatives of the formula (I) can be prepared by the procedures described in the general methods presented below or by the specific methods described in the Example synthesis part and Intermediate synthesis part, or by routine modifications thereof. The present invention also encompasses any one or more of these processes for preparing the pyrazolopyridine derivatives of formula (I), in addition to any novel intermediates used therein.

In the following general methods, descriptors are as previously defined for the pyrazolopyridine derivatives of the formula (I) unless otherwise stated.

In Step A-a, a compound of formula (I) can be prepared from a compound of formula

(IV) by Mitsunobu reaction with a compound of formula (V) using a suitable reagent in organic solvent in the presence of coupling reagent, but not limited to, such as diethyl azodicarboxylate triphenylphosphine, diisopropyl azodicarboxylate triphenylphosphine, di-ter-butyl azodicarboxylate triphenylphosphine, and cyanomethylenetributylphosphorane. Examples of suitable organic solvent include such as THF, 1,4-dioxane, DMF, MeCN, and toluene. The reaction can be carried out at a temperature of from about −20 to 180° C., more preferably from about 20 to 150° C. Reaction times are, in general, from about 30 minutes to 48 hours, more preferably from about 30 minutes to 24 hours.

When LG is such as O-trifluoromethanesulfonate, O-tosylate, O-mesylate, iodide, bromide, and chloride, in Step A-b, a compound of formula (VI) can be prepared by sulfonylation or substitution with halogen of a compound of formula (IV) under, for example, known sulfonylation condition or known halogenation conditions in an inert solvent. In case of sulfonylation, the reaction can be carried out in the presence of a base in an inert solvent. A preferred base is selected from, for example, but not limited to: an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, potassium fluoride, sodium hydride or potassium hydride; or an amine such as TEA, tributylamine, diisopropylethylamine, 2,6-lutidine, pyridine or dimethylaminopyridine. Examples of suitable inert aqueous or non-aqueous organic solvents include: alcohols, such as methanol or ethanol; ethers, such as THF or 1,4-dioxane; acetone; DMF; halogenated hydrocarbons, such as DCM, 1,2-dichloroethane or chloroform; and pyridine; or mixtures thereof. The reaction can be carried out at a temperature in the range of from about −10° C. to 200° C., preferably in the range of from about 20 to 100° C. Reaction times are, in general, from about 10 minutes to 4 days, preferably from about 10 minutes to 24 hours. In case of halogenation, example of halogen source is such as thionyl chloride, N-bromosuccinimide, N-chlorosuccinimide, iodine, bromine, phosphorous trichloride, phosphorous tribromide, carbon tetrachloride, or carbon tetrabromide. In the halogenation reaction, the reaction can be carried out in the presence of reducing agent such as triphenylphosphine. Examples of suitable organic solvent include such as THF, 1,4-dioxane, DCM, 1,2-dichloroethane, carbon tetrachloride, toluene, and DMF.

In Step A-c, a compound of formula (I) can be prepared from a compound of formula (VI) and formula (V) in the presence of a suitable base in an inert solvent. Examples of a suitable base include, but not limited to, such as sodium hydride, potassium carbonate, potassium bicarbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, tripotassium phosphate, potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, and dicyclohexylamine. Examples of suitable organic solvent include such as THF, 1,4-dioxane, DMF, MeCN, DMA, and toluene. The reaction can be carried out at a temperature of from about −20 to 150° C., more preferably from about 0 to 100° C. Reaction times are, in general, from about 30 minutes to 48 hours, more preferably from about 30 minutes to 24 hours.

In Step B-a, a compound of formula (VIII) can be prepared from a compound of formula (IV) and a compound of formula (VII) by Mitsunobu reaction as described in Step A-a.

In Step B-b, a compound of formula (VIII) can be prepared from a compound of formula (VI) and a compound of formula (VII) as described in Step A-c.

When —B—C—R⁶ component of formula (I) is —NHR²—(C═O)—R⁶, in Step B-c, a compound of (I-a) can be prepared by coupling of formula (VIII) with a suitable reagent of formula (IX) under coupling conditions in suitable organic solvents in the presence of a suitable transition metal catalyst and in the presence or absence of a base. Examples of suitable transition metal catalysts include, but not limited to: tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, copper(0), copper(I) acetate, copper(I) bromide, copper(I) chloride, copper(I) iodide, copper(I) oxide, copper(II) trifluoromethanesulfonate, copper(II) acetate, copper(II) bromide, copper(II) chloride, copper(II) iodide, copper(II) oxide, copper(II) trifluoromethanesulfonate, palladium(II) acetate, palladium(II) chloride, bis(acetonitrile)dichloropalladium(II ), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. Preferred catalysts are tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, palladium(II) acetate, palladium(II) chloride, bis(acetonitrile)dichloropalladium(0), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0) and [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. Examples of suitable carboxamide represented by formula (IX) include, but not limited to, carboximides such as acetamide, propionamide, isobutyramide and cyclopropanecarboxamide. Examples of suitable organic solvent include: THF; 1,4-dioxane; DMF; MeCN; alcohols, such as methanol or ethanol; halogenated hydrocarbons, such as DCM, 1,2-dichloroethane, chloroform or carbon tetrachloride; and diethyl ether; in the presence or absence of base such as tripotassium phosphate, sodium bicarbonate, sodium cabonate or potassium carbonate. This reaction can be carried out in the presence of a suitable additive. Examples of such an additive include, but not limited to: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, triphenylphosphine, tri-tert-butylphosphine, 1,1′-bis(diphenylphosphino)ferrocene, tri-2-furylphosphine, tri-o-tolylphosphine, 2-(dichlorohexylphosphino)biphenyl, and triphenylarsine. The reaction can be carried out at a temperature of from about 50 to 200° C., more preferably from about 80 to 150° C. Reaction times are, in general, from about 5 minutes to 48 hours, more preferably from about 30 minutes to 24 hours. In an alternative case, the reaction can be carried out with microwave system. The reaction can be carried out at a temperature in the range from about 100 to 200° C., preferably in the range from about 120 to 180° C. Reaction times are, in general, from about 10 minutes to 3 hours, preferably from about 15 minutes to 1 hour.

When —B—C—R⁶ component of formula (I) is —(C═O)—NR²R⁶, in Step B-d, a compound of (I-c) can be prepared from a compound of formula (VIII) and a compound of formula (XI) by CO insertion reaction in suitable organic solvents in the presence of suitable transition metal catalyst in the presence or absence of a base under carbon monoxide atmosphere. Example of suitable transition metal catalysts include, but not limited to: palladium metal, palladium-carbon, palladium(II) acetate, tris(dibenzylideneacetone)dipalladiumchloroform, [1,2-bis(diphenylphosphino)ethane]palladium dichloride, bis(tri-o-toluylphosphine)palladium dichloride, bis(triphenylphosphine)palladium dichloride, tetrakis(triphenylphosphine)palladium, dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium, or a catalyst produced in solution by adding a ligand into the reaction solution of these. The ligand added into the reaction solution may be a phosphoric ligand such as 1,1′-bis(diphenylphosphino)ferrocene, bis(2-diphenylphosphinophenyl)ether, 2,2′-bis(diphenylphosphino)-1,1′-binaphthol, 1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane, tri-o-toluylphosphine, triphenylphosphine, 2-diphenylphosphino-2′-methoxy-1,1′-binaphthyl or 2,2-bis (diphenylphosphino)-1,1′-binaphthyl. Examples of suitable organic solvent include: THF; 1,4-dioxane; DMF; DMA; MeCN; toluene; halogenated hydrocarbons, such as DCM, 1,2-dichloroethane, chloroform or carbon tetrachloride; and diethyl ether; in the presence or absence of base such as triethylamine, N,N-diisopropylethylamine, tripotassium phosphate, sodium bicarbonate, sodium cabonate or potassium carbonate. This reaction can be carried out in the presence of a suitable additive agent. Examples of such additive agents include: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, triphenylphosphine, tri-tert-butylphosphine, 1,1′-bis(diphenylphosphino)ferrocene, tri-2-furylphosphine, tri-o-tolylphosphine, 2-(dichlorohexylphosphino)biphenyl, and triphenylarsine. The reaction can be carried out at a temperature of from about 50 to 200° C., more preferably from about 60 to 150° C. Reaction times are, in general, from about 5 minutes to 48 hours, more preferably from about 30 minutes to 24 hours. Instead of carbon monoxide, other carbon monoxide source such as molybdenumhexacarbonyl and DMFpotassium tert-butoxide can be employed.

In an alternative case, the reaction can be carried out with microwave system. The reaction can be carried out at a temperature in the range from about 100 to 200° C., preferably in the range from about 120 to 180° C. Reaction times are, in general, from about 10 minutes to 3 hours, preferably from about 15 minutes to 1 hour.

In Step B-e, a compound of formula (I-b) can be prepared from a compound of formula (VIII) and alcohol of formula (X) by CO insertion reaction as described in Step B-d. Alternatively, the reaction can be carried out with other carbon monoxide source such as phenyl formate triethylamine and molybdenum hexacarbonyl.

In Step B-f, a compound of formula (I-c) can be prepared from a compound of formula (I-b) and formula (XI) in suitable solvents. Examples of suitable solvents include, but not limited to: THF, 1,4-dioxane, DMF, MeCN, MeOH, EtOH, and water. The reaction can be carried out at a temperature of from about 0 to 200° C., more preferably from about 20 to 150° C. Reaction times are, in general, from about 5 minutes to 48 hours, more preferably from about 30 minutes to 24 hours.

In Step B-g, a compound of formula (XII) can be prepared by hydrolysis of the ester compound of formula (I-b). The hydrolysis can be carried out by the conventional procedures. In a typical procedure, the hydrolysis is carried out under basic conditions, e.g. in the presence of sodium hydroxide, potassium hydroxide or lithium hydroxide. Suitable solvents include, for example, but not limited to: water, alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and ethylene gylcol; ethers such as THF, DME, and 1,4-dioxane; amides such as DMF and hexamethylphospholic triamide; and sulfoxides such as DMSO. Preferred solvents are water, methanol, ethanol, propanol, THF, DME, 1,4-dioxane, DMF, and DMSO. This reaction can be carried out at a temperature in the range of from about 20 to 100° C. for from about 30 minutes to 24 hours.

In Step B-h, a compound of formula (I-c) can be prepared from a compound of formula (XII) by amidation with a compound of formula (XI) using a suitable condensation agent such as HBTU and EDC-HOBT, preferably under the presence of a base such as triethylamine and N,N-diisopropylethylamine in a suitable solvent such as DMF, DMA and DCM at a temperature of from about 5 to 60° C. for about 1-24 hours. In addition, a compound of formula (I-c) can be also prepared from a compound of formula (III) by amidation with an acid halide prepared from a compound of formula (XII) using thionyl chloride or oxalyl chloride, preferably under the presence of a base such as triethylamine, pyridine, and N,N-diisopropylethylamine in a suitable solvent such as DCM at a temperature of from about 5 to 40° C. for about 1-24 hours.

In Step C-a, a compound of formula (XV) can be prepared from amine of formula (XIII) and a compound of formula (XIV) in suitable solvents such as toluene, THF, dioxane, diethyl ether, DCM, 1,2-dichloroethane, chloroform, hexane, MeOH, and EtOH. The reaction can be carried out in a presence of a suitable additive reagent. Examples of such additive reagents include, but not limited to, titanium(IV) isopropoxide, titanium(IV) ethoxide, molecular sieves, magnesium sulfate, copper(II) sulfate, hydrochloric acid, acetic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, and 10-camphorsulfonic acid. This reaction can be carried out at a temperature in the range of from about 0 to 150° C. for from about 30 minutes to 48 hours.

In Step C-b, a compound of formula (I) can be prepared from a compound of formula (XV) in a presence of a suitable reagent such as triethyl phosphite and iodobenzene diacetate in an inert solvent or without a solvent. A preferred solvent is selected from DMF, DMA, MeOH, EtOH, DCM, 1,2-dichloroethane, and toluene. This reaction can be carried out at a temperature in the range of from about 0 to 150° C. for from about 30 minutes to 48 hours.

In Step C-c, a compound of formula (XVII) can be prepared from a compound of formula (XIII) and a compound of formula (XVI) as described in Step C-a.

In Step C-d, a compound of formula (VIII) can be prepared from a compound of formula (XVII) as described in Step C-b.

In Step C-e, a compound of formula (I) can be prepared from a compound of formula (VIII) in a similar manner to B-c, B-d, B-e, B-f, B-g, and B-h in Scheme B.

In Step D-a, a compound of formula (XIX) can be prepared from a compound of formula (XIII) and a compound of formula (XVIII) as described in Step C-a.

In Step D-b, a compound of formula (I) can be prepared from a compound of formula (XIX) with or without a suitable additive in a suitable solvent. Examples of suitable additive include, but not limited to, such as copper(I) iodide/N,N,N′,N′-tetramethylethylenediamine. Examples of a suitable solvent include, but not limited to, such as toluene, 1,2-dichlorobenzene, DMF, DMA, THF, 1,4-dioxane, DCM, and 1,2-dichloroethane. The reaction can be carried out at a temperature of from about 20 to 180° C. Reaction times are, in general, from about 30 minutes to 48 hours.

In Step D-c, a compound of formula (XXI) can be prepared from a compound of formula (XIII) and a compound of formula (XX) as described in Step C-a.

In Step D-d, a compound of formula (VIII) can be prepared from a compound of formula (XXI) as described in Step D-b.

In Step D-e, a compound of formula (I) can be prepared from a compound of formula (VIII) in a similar manner to B-c, B-d, B-e, B-f, B-g, and B-h in Scheme B.

In Step E-a, a compound of formula (I) can be prepared from a compound of formula (XXII) and a compound of formula (XXIII) in a suitable organic solvent. Examples of suitable organic solvent include, but not limited to, such as MeOH, EtOH, toluene, THF, 1,4-dioxane, DMF, MeCN, 1,2-dichloroethane, and toluene. The reaction can be carried out at a temperature of from about 20 to 180° C., more preferably from about 50 to 150° C. Reaction times are, in general, from about 30 minutes to 48 hours, more preferably from about 30 minutes to 24 hours.

In Step E-b, a compound of formula (VIII) can be prepared from a compound of formula (XXII) and a compound of formula (XXIV) as described in Step E-a.

In Step E-c, a compound of formula (I) can be prepared from a compound of formula (VIII) in a similar manner to B-c, B-d, B-e, B-f, B-g, and B-h in Scheme B.

The key intermediate amines of formula (XIII) can be prepared by the following general synthetic route of Scheme F and G.

When —(O)_(r)—(CR³R⁴)_(k)—NH₂ component of formula (XIII) is —(CR³R⁴)—NH₂, a compound of formula (XIII-a) can be prepared according to Scheme F and G.

In Step F-a, a compound of formula (XXVII) can be prepared by hydrolysis of the ester compound of formula (XXVI) as described in Step B-g.

In Step F-b, a compound of formula (XXIX) can be prepared from acid of the formula (XXVII) and N,O-dimethylhydroxylamine (XXVIII) by amidation (Weinreb amide formation) as described in Step B-h.

In Step F-c, a compound of formula (XXXI) can be prepared from compound of formula (XXIX) by the treatment with a suitable alkyl-metal reagent (XXX) in an inert solvent. Examples of suitable alkyl-metal reagent include, but not limited to, such as methyllitium, ethyllithium, methylmagnesium chloride, methylmagnesium bromide, and methylmagnesium iodide. Examples of inert solvent include, but not limited to, such as THF, diethyl ether, DME, and 1,4-dioxane. The reaction can be carried out at a temperature of from about -40 to 100° C., more preferably from about 0 to 50° C. Reaction times are, in general, from about 5 minutes to 48 hours, more preferably from about 30 minutes to 24 hours.

In Step F-d, a compound of formula (XXXIII) can be prepared as a single diastereomer from carbonyl compound of formula (XXXI) and a chiral tert-butanesulfinamide (XXXII) by the conventional methods known to those skilled in the art (Pure Appl. Chem., 75, 39-46, 2003; Tetrahedron Lett., 45, 6641-6643, 2004). In the following intermediate and example sections, a compound name of formula (XXXIII) is described as an (R) or (S) isomer, which represents the configuration of a sulfur atom.

In Step F-e, a compound of formula (XIII-a) can be prepared as a single enantiomer from a compound of formula (XXXIII) by the treatment with acidic condition by the conventional methods known to those skilled in the art (Pure Appl. Chem., 75, 39-46, 2003; Tetrahedron Lett., 45, 6641-6643, 2004).

In Step G-a, a compound of formula (XXXV) can be prepared from aldehyde of formula (XXXIV) and chiral tert-butanesulfinamide (XXXII) by the conventional methods known to those skilled in the art (Pure Appl. Chem., 75, 39-46, 2003; Tetrahedron Lett., 45, 6641-6643, 2004).

In Step G-b, a compound of (XXXVI) can be prepared as a single diastereomer from chiral sulfinyl imine of formula (XXXV) and alkyl-metal reagent or hydride reagent by the conventional methods known to those skilled in the art (Pure Appl. Chem., 75, 39-46, 2003; Tetrahedron Lett., 45, 6641-6643, 2004). In the following intermediate and example sections, a compound name of formula (XXXVI) is described as an (R) or (S) isomer, which represents the configuration of a sulfur atom.

In Step G-c, a compound of formula (XIII-a) can be prepared as a single enantiomer from a compound of formula (XXXVI) by the treatment with acidic condition by the conventional methods known to those skilled in the art (Pure Appl. Chem., 75, 39-46, 2003; Tetrahedron Lett., 45, 6641-6643, 2004).

When —(O)_(r)—(CR³R⁴)_(k)—OH component of the key intermediate alcohols of formula (IV) is —(CR³R⁴)—OH, a compound of formula (IV-a) can be prepared by the following general synthetic route of Scheme H.

The key intermediate alcohols of formula (IV-a) can be prepared by the following general synthetic route of Scheme H.

In Step H-a, a compound of formula (IV-a) can be prepared by reduction of a compound of formula (XXXVII). The reduction may be carried out in the presence of a suitable reducing reagent in an inert solvent or without solvent. A preferred reducing agent is selected from, for example, but not limited to, such as sodium borohydride, lithium aluminum hydride, lithium borohydride, boran-complex, and diisobutylaluminium hydride. Reaction temperatures are generally in the range of from about -78 to 100° C., preferably in the range of from about -70 to 60° C. Reaction times are, in general, from about 30 minute to a day. Examples of suitable solvents include, but not limited to: THF; 1,4-dioxane; DMF; MeCN; alcohols, such as MeOH or EtOH, and halogenated hydrocarbons, such as DCM, 1,2-dichloroethane, chloroform or carbon tetrachloride.

In Step H-b, a compound of formula (XXXVIII) can be prepared by the hydrolysis of the ester compound of formula (XXXVII) as described in Step B-g.

In Step H-c, a compound of formula (IV-a) can be prepared by the reduction of the carboxylic acid of formula (XXXVIII) as described in Step H-a.

The key intermediate pyrazolopyridine of formula (V) and (VII) can be prepared by the following general synthetic route of Scheme J.

In Step J-a, a compound of formula (XLI) can be prepared by metalation of a compound of formula (XXXIX) and trapping by a carbonyl compound of formula (XL). Metalation can be carried out by a base such as n-butyllitium, sec-butyllithium, tert-butyllithium, and lithium diisopropylamide. Examples of the carbonyl compound of formula (XL) include, but not limited to, such as DMF, acetyl chloride, propionyl chloride, and benzoyl chloride. Examples of suitable organic solvent include such as THF, diethyl ether, 1,4-dioxane, and hexane. The reaction can be carried out at a temperature of from about -78 to 20° C. Reaction times are, in general, from about 30 minutes to 24 hours.

In Step J-b, a compound of formula (VII) can be prepared from the carbonyl compound of formula (XLI) and hydrazine as described in Step E-a.

In Step J-c, a compound of formula (V) can be prepared from the compound of formula (VII) in a similar manner to B-c, B-d, B-e, B-f, B-g, and B-h in Scheme B.

The key intermediate of formula (XVI) can be prepared by the following general synthetic route of Scheme K.

In Step K-a, a protecting group can be introduced by the conventional methods known to those skilled in the art (typical amino protecting groups described in “Protective Groups in Organic Synthesis Forth Edition” edited by T. W. Greene et al. (John Wiley & Sons, 2007)).

In Step K-b, a compound of formula (XLIV) can be prepared from the compound of formula (XLIII) and a compound of formula (XL) as described in Step J-a.

In Step K-c, a compound of formula (XVI) can be prepared by de-protection of a compound of formula (XLIV) by the conventional methods known to those skilled in the art (typical amino protecting groups described in “Protective Groups in Organic Synthesis Forth Edition” edited by T. W. Greene et al. (John Wiley & Sons, 2007)).

All starting materials and intermediates in the following syntheses may be commercially available or obtained by the conventional methods known to those skilled in the art, otherwise noted in the intermediate synthesis part.

INTERMEDIATE SYNTHESIS PART

Intermediate compounds are prepared as follows.

Intermediate-A1 (5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol <Step-1>: 5-methyl-6-(2,2,2-trifluoroethoxy)nicotinic acid

To a stirred mixture of sodium hydride (9.28 g, 232 mmol, 60% in oil, washed with hexane before use) in DMA (60 mL) is added 2,2,2-trifluoroethanol (6.68 mL, 93 mmol) at 0° C. and stirred at rt for 20 minutes. To the mixture is added a solution of 6-fluoro-5-methylnicotinic acid (12.0 g, 77 mmol) in DMA (160 mL) at rt and the resulting mixture is stirred at 70° C. for 6 hours and continued stirred at rt overnight. The reaction mixture is diluted with water (800 mL) and acidified by the addition of 2 M hydrochloric acid. The white precipitate is collected by the filtration, washed with water and hexane, and dried in vacuo at 50° C. for 3 hours to give 15.1 g (83% yield) of the title compound as a white solid.

The symbol ‘δ’ is written “deltas” hereafter.

¹H-NMR (300 MHz, CDCl₃) delta 8.72 (1H, s), 8.10 (1H, s), 4.84 (2H, q, J=8.8 Hz), 2.30 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 234 (M−H)⁻.

<Step-2>: (5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol

To a stirred solution of 5-methyl-6-(2,2,2-trifluoroethoxy)nicotinic acid (15.0 g, 63.8 mmol, Step-1) in THF (120 mL) is added portionwise lithium aluminum hydride (3.20 g, 84 mmol) at 0° C. The reaction mixture is stirred at rt for 2 hours. The reaction mixture is quenched with saturated aqueous ammonium chloride solution at 0° C. The resulting slurry is filtered through a pad of Celite and is washed with EtOAc (100 mL x 4). The combined filtrate is washed with water and brine, dried over sodium sulfate, then filtered and concentrated to give 13.51 g (96% yield) of the title compound as a pale yellow solid.

¹H-NMR (300 MHz, CDCl₃) delta 7.93 (1H, s), 7.51 (1H, s), 4.76 (2H, q, J=8.8 Hz), 4.63 (2H, br), 2.24 (3H, s) (a signal due to OH is not observed), MS (ESI) m/z: 222 (M+H)⁺.

Intermediate-A2 (6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methanol <Step-1>: 6-(2,2-difluoroethoxy)-5-methylnicotinic acid

The title compound is prepared in 94% yield (6.57 g, a white solid) from 6-fluoro-5-methylnicotinic acid (5.00 g, 32.2 mmol) and 2,2-difluoroethanol (5.29 g, 64.5 mmol) in a similar manner to Step-1 of Intermediate-A1.

¹H-NMR (300 MHz, DMSO-d₆) delta 13.09 (1H, br s), 8.56 (1H, d, J=2.2 Hz), 8.07 (1H, d, J=2.2 Hz), 6.42 (1H, tt, J=54.3, 3.7 Hz), 4.66 (2H, td, J=14.7, 3.7 Hz), 2.21 (3H, s), MS (ESI) m/z: 218 (M+H)⁺.

<Step-2>: methyl 6-(2,2-difluoroethoxy)-5-methylnicotinate

To a mixture of 6-(2,2-difluoroethoxy)-5-methylnicotinic acid (3.19 g, 14.7 mmol, Step-1) and potassium carbonate (4.06 g, 29.4 mmol) in DMF (37 mL) is added iodomethane (1.4 mL, 22 mmol), and the mixture is stirred at rt for 1 hour. The mixture is poured onto water (300 mL), and the aqueous layer is extracted with EtOAc (300 mL). The separated organic layer is washed with water (100 mL), dried over sodium sulfate, and concentrated in vacuo. The residue is purified by chromatography on silica gel eluting with n-hexane/EtOAc (10:1-4:1) to give 2.99 g (88% yield) of the title compound as a white solid.

¹H-NMR (300 MHz, CDCl₃) delta 8.64 (1H, d, J=1.8 Hz), 8.03 (1H, d, J=1.8 Hz), 6.15 (1H, tt, J=55.8, 4.4 Hz), 4.61 (2H, td, J=13.2, 4.4 Hz), 3.91 (3H, s), 2.25 (3H, s), MS (ESI) m/z: 232 (M+H)⁺.

<Step-3>: (6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methanol

The title compound is prepared in quantitative yield (2.62 g, colorless oil) from methyl 6-(2,2-difluoroethoxy)-5-methylnicotinate (2.99 g, 12.9 mmol, Step-2) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, CDCl₃) delta 7.92 (1H, d, J=1.8 Hz), 7.48 (1H, d, J=1.8 Hz), 6.14 (1H, tt, J=55.8, 4.0 Hz), 4.62-4.49 (4H, m), 2.22 (3H, s), 1.80 (1H, t, J=5.9 Hz), MS (ESI) m/z: 204 (M+H)⁺.

Intermediate-A3 (5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol <Step-1>: 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinic acid

To a suspension of sodium hydride (5.00 g, 60% in oil, 125 mmol) in DMA is added 2,2,2-trifluoroethanol (5.8 mL, 94 mmol) at 0° C. After stirring at 0° C. for 20 minutes, 5.6-dichloronicotinic acid (12.0 g, 62.5 mmol) is added to the mixture, and this is stirred at 90° C. for 2 hours. After cooling to rt, the mixture is poured onto 0.3 M hydrochloric acid (700 mL). The formed white precipitate is collected by filtration and washed with water and hexane to give 16.6 g (quantitative yield) of the title compound as a white solid. This is used for the next step without further purification.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.66 (1H, d, J=2.2 Hz), 8.32 (1H, d, J=2.2 Hz), 5.15 (2H, q, J=8.8 Hz), MS (ESI) m/z: 256 (M+H)⁺.

<Step-2>: (5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol

To a stirred solution of 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinic acid (5.00 g, 19.5 mmol, Step-1) in THF (50 mL) is added N,N′-carbonyldiimidazole (4.76 g, 29.3 mmol) at rt. After stirring at rt for 2 hours, a solution of sodium borohydride (3.70 g, 98.0 mmol) in water (50 mL) is added slowly to the mixture at 0° C. After stirring at 0° C. for 15 minutes, 2 M hydrochloric acid (50 mL) is added to the mixture at 0° C. After 30 minutes, the mixture is poured onto saturated sodium bicarbonate solution (100 mL) carefully. This is extracted with EtOAc (200 mL), and the organic layer is dried over sodium sulfate. After removal of the organic solvent, the residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (2:1) to give 4.63 g (98% yield) of the title compound as a pale yellow solid.

¹H-NMR (300 MHz, CDCl₃) delta 8.00 (1H, d, J=2.2 Hz), 7.76 (1H, d, J=2.2 Hz), 4.82 (2H, q, J=8.8 Hz), 4.66 (2H, s), MS (ESI) m/z: 242 (M+H)⁺.

Intermediate-A4 (5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methanol <Step-1>: 5-chloro-6-(2,2-difluoroethoxy)nicotinic acid

The title compound is prepared in 83% yield (4.12 g, a white solid) from 5,6-dichloronicotinic acid (4.00 g, 20.8 mmol) and 2,2-difluoroethanol in a similar manner to Step-1 of Intermediate-A3.

¹H-NMR (300 MHz, DMSO-d₆) delta 13.4 (1H, br s), 8.65 (1H, d, J=1.8 Hz), 8.28 (1H, d, J=1.8 Hz), 6.44 (1H, tt, J=54.3, 3.3 Hz), 4.73 (2H, td, J=15.0, 3.3 Hz), MS (ESI) m/z: 236 (M−H)⁻.

<Step-2>: methyl 5-chloro-6-(2,2-difluoroethoxy)nicotinate

To a solution of 5-chloro-6-(2,2-difluoroethoxy)nicotinic acid (1.5 g, 6.31 mmol, Step-1) in MeOH (100 ml) is added dropwise thionyl chloride (1.38 ml, 18.9 mmol) at 0° C. Then the reaction mixture is refluxed with stirring for 2 hours. After removing solvent to give 1.57 g (quantitative yield) of the title compound as a white solid.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.68 (1H, d, J=2.2 Hz), 8.33 (1H, d, J=2.2 Hz), 6.44 (1H, tt, J=54.3, 3.3 Hz), 4.74 (2H, td, J=14.7, 3.3 Hz), 3.86 (3H, s), MS (ESI) m/z: 252 (M+H)⁺.

<Step-3>: (5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methanol

The title compound is prepared in 62% yield (0.87 g, colorless oil) from methyl 5-chloro-6-(2,2-difluoroethoxy)nicotinate (1.57 g, 6.25 mmol, Step-2) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, CDCl₃) delta 7.99 (1H, d, J=2.2 Hz), 7.74 (1H, d, J=2.2 Hz), 6.16 (1H, tt, J=55.4, 4.4 Hz), 4.65 (2H, d, J=5.5 Hz), 4.60 (2H, td, J=13.2, 4.0 Hz), a signal due to OH is not observed, MS (ESI) m/z: 224 (M+H)⁺.

Intermediate-A5 (5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol <Step-1>: 2-chloro-5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinic acid

A mixture of 2,6-dichloro-5-fluoronicotinic acid (25.0 g, 119 mmol), 2,2,2-trifluoroethanol (17.1 mL, 238 mmol) and sodium hydroxide (14.3 g, 357 mmol) in water (600 mL) is stirred at 80° C. for 40 hours. After cooling to 0° C., the mixture is acidified with conc. hydrochloric acid (pH 2). The resulting white precipitate is collected by filtration and dried to give 32.2 g of the title compound as a crude. This is used for the next step without further purification.

MS (ESI) m/z: 274 (M+H)⁺.

<Step-2>: 5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinic acid

A mixture of 2-chloro-5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinic acid (32.2 g, 118 mmol, Step-1), triethylamine (23 mL, 165 mmol), and 10% Pd-C(12.5 g) in EtOH is stirred at rt for 5 hours under hydrogen atmosphere. Then the mixture is filtered through a pad of Celite, and the filtrate is concentrated in vacuo. The residue is dissolved in water (300 mL), and the solution is acidified by conc. Hydrochloric acid. The formed white precipitate is collected by filtration to give 21.0 g (75%) of the title compound as a white solid.

¹H-NMR (300 MHz, DMSO-d₆) delta 13.40 (1H, br), 8.55 (1H, d, J=1.8 Hz), 8.13 (1H, dd, J=10.3, 1.8 Hz), 5.16 (2H, q, J=9.2 Hz), MS (ESI) m/z: 238 (M−H)⁻.

<Step-3>: (5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol

The title compound is prepared in 91% yield (1.11 g, a brown oil) from 5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinic acid (1.29 g, 5.39 mmol, Step-2) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, CDCl₃) delta 7.88 (1H, s), 7.48 (1H, dd, J=9.9, 1.5 Hz), 4.84 (2H, q, J=8.4 Hz), 4.68 (2H, d, J=5.9 Hz), 1.76 (1H, m), MS (ESI) m/z: 226 (M+H)+

Intermediate-A6 (6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methanol <Step-1>: methyl 6-(3,3,3-trifluoropropoxy)nicotinate

Potassium tert-butoxide (2.45 g, 21.9 mmol) is added to a solution of 3,3,3-trifluoropropan-1-ol (1.67 mL, 18.9 mmol) in THF (30 mL) and stirred for 5 minutes. Then methyl 6-chloronicotinate (2.5 g, 14.6 mmol) is added there and stirred for 2 hours. The reaction mixture is poured into water, extracted with EtOAc. The organic layer is dried over sodium sulfate and concentrated in vacuo to give 2.21 g (61% yield) of the title compound as a colorless oil. This material is used for the next reaction (Step-2) without further purification.

¹H-NMR (300 MHz, CDCl₃) delta 8.81 (1H, d, J=2.2 Hz), 8.17 (1H, dd, J=8.8, 2.2 Hz), 6.79 (1H, d, J=8.8 Hz), 4.62 (2H, t, J=6.2 Hz), 3.91 (3H, s), 2.63 (2H, m), MS (ESI) m/z: 250 (M+H)⁺.

<Step-2>: 6-(3,3,3-trifluoropropoxy)nicotinic acid

To a solution of methyl 6-(3,3,3-trifluoropropoxy)nicotinate (1.37 g, 5.50 mmol, Step-1) in MeOH (30 mL) is added 2 M sodium hydroxide (5 mL), and stirred for 2 hours at 60° C. After removal of the solvent, the residue is dissolved in water (30 mL) and acidified with conc. hydrochloric acid (pH 2). The resulting white precipitate is collected by filtration and dried to give 1.11 g (86% yield) of the title compound as a white solid.

¹H-NMR (300 MHz, CDCl₃) delta 8.90 (1H, d, J=2.2 Hz), 8.23 (1H, dd, J=8.8, 2.2 Hz), 6.83 (1H, d, J=8.8 Hz), 4.65 (2H, t, J=6.2 Hz), 2.65 (2H, m), MS (ESI) m/z: 236 (M+H)⁺.

<Step-3>: (6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methanol

The title compound is prepared in 91% yield (858 mg, 4.25 mmol, a brown oil) from 6-(3,3,3-trifluoropropoxy)nicotinic acid (1.00 g, 4.25 mmol, Step-2) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, CDCl₃) delta 8.11 (1H, d, J=2.2 Hz), 7.64 (1H, dd, J=8.4, 2.6 Hz), 6.77 (1H, d, J=8.1 Hz), 4.64 (2H, s), 4.55 (2H, t, J=6.6 Hz), 2.70-2.54 (2H, m), 1.67 (1H, br s), MS (ESI) m/z: 222 (M+H)⁺.

Intermediate-A7 1(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer; antipode of Intermediate-A27) <Step-1>: N-methoxy-N,5-dimethyl-6-(2,2,2-trifluoroethoxy)nicotinamide

A mixture of 5-methyl-6-(2,2,2-trifluoroethoxy)nicotinic acid (2.27 g, 9.67 mmol, Step-1 of Intermediate-A1), N,O-dimethylhydroxylamine hydrochloride (1.04 g, 10.64 mmol), HBTU (5.50 g, 14.51 mmol) and triethylamine (5.39 mL, 38.7 mmol) in DCM (30 mL) is stirred at rt for 1.5 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate solution (300 mL) and extracted with DCM (500 mL). The organic layer is washed with saturated aqueous sodium hydrogen carbonate (300 mL×2) and dried over sodium sulfate, and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (4:1) to give 2.03 g (76% yield) of the title compound as a colorless oil.

¹H-NMR (300 MHz, CDCl₃) delta 8.43 (1H, d, J=2.2 Hz), 7.86 (1H, m), 4.82 (2H, q, J=8.4 Hz), 3.60 (3H, s), 3.38 (3H, s), 2.26 (3H, s), MS (ESI) m/z: 279 (M+H)⁺.

<Step-2>: 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone

To a solution of N-methoxy-N,5-dimethyl-6-(2,2,2-trifluoroethoxy)nicotinamide (2.03 g, 7.31 mmol, Step-1) in THF (25 mL) is added dropwise a solution of methylmagnesium bromide in THF (1.12 M, 13.1 mL, 14.6 mmol) at 0° C. After stirring at rt for 1.5 h, the reaction is quenched with saturated aqueous sodium bicarbonate solution (150 mL), and the aqueous layer is extracted with EtOAc (150 mL×2). The combined organic layer is dried over sodium sulfate and concentrated in vacuo. The residual solid is washed with hexane to give 1.47 g (86% yield) of the title compound as a white solid.

¹H-NMR (300 MHz, CDCl₃) delta 8.59 (1H, d, J=2.0 Hz), 8.03 (1H, d, J=2.2 Hz), 4.84 (2H, q, J=8.4 Hz), 2.57 (3H, s), 2.27 (3H, s), MS (ESI) m/z: 234 (M+H)⁺.

<Step-3>: (R)-2-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)

To a mixture of 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (1.47 g, 6.32 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide (1.15 g, 9.48 mmol) in THF (10 mL) is added titanium(IV) ethoxide (1.99 mL, 9.48 mmol), and the mixture is stirred at 70° C. for 22 hours. After cooling to 0° C., sodium borohydride (717 mg, 19.0 mmol) is added to the mixture. After stirring at 0° C. for 1 h, the reaction is quenched with saturated aqueous sodium bicarbonate solution (150 mL), and the aqueous layer is extracted with EtOAc (150 mL). The separated organic layer is washed with water, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (4:1-1:1.5) to give 1.70 g (79%) of the title compound as a colorless oil.

¹H-NMR (300 MHz, CDCl₃) delta 7.94 (1H, d, J=2.2 Hz), 7.45 (1H, d, J=2.2 Hz), 4.76 (2H, q, J=8.8 Hz), 4.56-4.43 (1H, m), 3.32 (1H, d, J=2.6 Hz), 2.24 (3H, s), 1.51 (3H, d, J=6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 339 (M+H)⁺.

<Step-4>: 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer; antipode of Intermediate-A27)

A mixture of (R)-2-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-propane-2-sulfinamide (single diastereomer, Step-3) (1.70 g, 5.01 mmol) and 8 M HCl-MeOH (10 mL) is stirred at rt for 1 hour. After removing the solvent, the residual solid is crystallized from EtOAc/hexane to give 1.27 g (94%) of the title compound as a white solid.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.56 (2H, br s), 8.16 (1H, d, J=2.0 Hz), 7.87 (1H, d, J=2.0 Hz), 5.03 (2H, q, J=9.2 Hz), 4.50-4.28 (1H, m), 2.20 (3H, s), 1.50 (3H, d, J=7.0 Hz), MS (ESI) m/z: 235 (M+H)⁺.

Intermediate-A8 (6-(2,2-difluoroethoxy)-5-fluoropyridin-3-yl)methanol <Step-1>: 2-chloro-6-(2,2-difluoroethoxy)-5-fluoronicotinic acid

The title compound is prepared in 55% yield (6.76 g, a white solid) from 2,6-dichloro-5-fluoronicotinic acid (10.0 g, 47.6 mmol) and 2,2-difluoroethanol in a similar manner to Step-1 of Intermediate-A5.

¹H-NMR (300 MHz, CDCl₃) delta 8.10 (1H, d, J=9.5 Hz), 6.17 (1H, tt, J=55.0, 4.1 Hz), 4.68 (2H, td, J=12.8, 4.1 Hz) (a signal due to COOH is not observed), MS (ESI) m/z: 256 (M+H)⁺.

<Step-2>: 6-(2,2-difluoroethoxy)-5-fluoronicotinic acid

The title compound is prepared in 55% yield (2.1 g, a white solid) from 2-chloro-6-(2,2-difluoroethoxy)-5-fluoronicotinic acid (4.5 g, 17.6 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A5.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.55 (1H, d, J=2.2 Hz), 8.08 (1H, dd, J=12.5, 2.2 Hz), 6.44 (1H, tt, J=54.3, 3.3 Hz), 4.75 (2H, td, J=15.0, 3.3 Hz) (a signal due to COOH is not observed), MS (ESI) m/z: 220 (M−H)⁻.

<Step-3>: methyl 6-(2,2-difluoroethoxy)-5-fluoronicotinate

The title compound is prepared in 71% yield (1.6 g, a white solid) from 6-(2,2-difluoroethoxy)-5-fluoronicotinic acid (2.1 g, 9.7 mmol, Step-2) in a similar manner to Step-2 of Intermediate-A4.

¹H-NMR (300 MHz, CDCl₃) delta 8.59 (1H, s), 7.95 (1H, d, J=11.1 Hz), 6.18 (1H, tt, J=55.4, 4.0 Hz), 4.68 (2H, td, J=13.2, 3.7 Hz), 3.94 (3H, s), MS (ESI) m/z: 236 (M+H)⁺.

<Step-4>: (6-(2,2-difluoroethoxy)-5-fluoropyridin-3-yl)methanol

The title compound is prepared in 88% yield (1.24 g, a colorless oil) from methyl 6-(2,2-difluoroethoxy)-5-fluoronicotinate (1.6 g, 6.8 mmol, Step-3) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, CDCl₃) delta 7.87 (1H, s), 7.45 (1H, d, J=10.3 Hz), 6.16 (1H, tt, J=55.4, 4.4 Hz), 4.66 (2H, d, J=5.9 Hz), 4.60 (2H, td, J=13.2, 3.7 Hz) (a signal due to OH is not observed), MS (ESI) m/z: 208 (M+H)⁺, 206 (M−H)⁻.

Intermediate-A9 (6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanol

The title compound is prepared in 78% yield (12.6 g, a yellow semi-solid) from 6-(2,2,3,3-tetrafluoropropoxy)nicotinic acid (1.29 g, 5.39 mmol) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, CDCl₃) delta 8.13 (1H, d, J=2.2 Hz), 7.69 (1H, dd, J=8.8, 2.2 Hz), 6.84 (1H, d, J=8.8 Hz), 6.02 (1H, tt, J=53.1, 4.6 Hz), 4.78-4.66 (4H, m), 1.69 (1H, t, J=5.9 Hz), MS (ESI) m/z: 240 (M+H)⁺.

Intermediate-A10 (6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)methanol <Step-1>: methyl 6-(2,2,3,3,3-pentafluoropropoxy)nicotinate

To a stirred suspension of sodium hydride (3.85 g, 96 mmol, 60% in oil) in DMA (120 mL) is added dropwise 2,2,3,3,3-pentafluoropropan-1-ol (6.4 mL, 64 mmol) at 0° C. After stirring for 10 minutes, a solution of methyl 6-chloronicotinate (5.5 g, 32 mmol) in DMA (40 mL) is added dropwise at 0° C., and the mixture is stirred for 30 minutes at rt. Then the mixture is stirred at 90° C. for 2 hours. After cooled to rt, 2 M aqueous sodium hydroxide is added (pH is around 6). The mixture is extracted with n-hexane/EtOAc (1:2, 200 mL). The organic layer is washed with water, brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by column chromatography on NH-gel eluting with n-hexane/EtOAc (30:1) to give 3.07 g (34% yield) of the title compound as a brown oil.

¹H-NMR (300 MHz, CDCl₃) delta 8.12 (1H, d, J=2.2 Hz), 8.24 (1H, dd, J=8.4, 2.6 Hz), 6.90 (1H, d, J=8.1 Hz), 4.90 (2H, t, J=12.5 Hz), 3.93 (3H, s), MS (ESI) m/z: 286 (M+H)⁺.

<Step-2>: (6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)methanol

The title compound is prepared in 83% yield (2.31 g, a brown oil) from methyl 6-(2,2,3,3,3-pentafluoropropoxy)nicotinate (3.07 g, 10.8 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, CDCl₃) delta 8.13 (1H, d, J=1.5 Hz), 7.69 (1H, dd, J=8.8, 2.2 Hz), 6.87 (1H, d, J=8.8 Hz), 4.84 (2H, t, J=12.8 Hz), 4.66 (2H, d, J=5.1 Hz), 1.73 (1H, t, J=5.1 Hz), MS (ESI) m/z: 258 (M+H)⁺.

Intermediate-A11 (+)-1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: 6-(2,2-difluoroethoxy)-N-methoxy-N,5-dimethylnicotinamide

The title compound is prepared in 98% yield (1.20 g, a white solid) from 6-(2,2-difluoroethoxy)-5-methylnicotinic acid (1.02 g, 4.70 mmol, Step-1 of Intermediate-A2) in a similar manner to Step-1 of Intermediate-A7.

¹H-NMR (300 MHz, CDCl₃) delta 8.43 (1H, d, J=2.2 Hz), 7.84 (1H, br s), 6.16 (1H, tt, J=55.8, 4.4 Hz), 4.60 (2H, td, J=13.2, 4.4 Hz), 3.58 (3H, s), 3.37 (3H, s), 2.25 (3H, s), MS (ESI) m/z: 261 (M+H)⁺.

<Step-2>: 1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethanone

The title compound is prepared in quantitative yield (0.99 g, a white solid) from 6-(2,2-difluoroethoxy)-N-methoxy-N,5-dimethylnicotinamide (1.20 g, 4.61 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A7.

¹H-NMR (270 MHz, CDCl₃) delta 8.58 (1H, d, J=2.0 Hz), 8.01-8.00 (1H, m), 6.16 (1H, tt, J=55.4, 4.0 Hz), 4.63 (2H, td, J=13.2, 4.0 Hz), 2.57 (3H, s), 2.26 (3H, s), MS (ESI) m/z: 216 (M+H)⁺.

<Step-3>: (R)—N-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 82% yield (1.22 g, colorless oil) from 1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethanone (0.99 g, 4.61 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-3 of Intermediate-A7.

¹H-NMR (300 MHz, CDCl₃) delta 7.97 (1H, d, J=2.2 Hz), 7.43 (1H, br s), 6.14 (1H, tt, J=55.8, 4.4 Hz), 4.59-4.46 (3H, m), 3.32 (1H, br s), 2.22 (3H, s), 1.50 (3H, d, J=6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 321 (M+H)⁺.

<Step-4>: (+)-1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 94% yield (0.91 g, a white solid) from (R)—N-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (1.22 g, 3.80 mmol, Step-3) in a similar manner to Step-4 of Intermediate-A7.

¹H-NMR (270 MHz, DMSO-d₆) delta 8.58 (2H, br s), 8.13 (1H, d, J=2.0 Hz), 7.82 (1H, br s), 6.40 (1H, tt, J=54.7, 3.3 Hz), 4.60 (2H, td, J=15.2, 3.3 Hz), 4.42-4.36 (1H, m), 2.19 (3H, s), 1.52 (3H, d, J=6.6 Hz), MS (ESI) m/z: 217 (M+H)⁺.

[α]_(D) ²⁶=+3.09 (c=1.18, methanol)

Intermediate-A12 (6-(4-fluorophenoxy)-5-methylpyridin-3-yl)methanol <Step-1>: methyl 6-(4-fluorophenoxy)-5-methylnicotinate

A mixture of methyl 6-fluoro-5-methylnicotinate (2.40 g, 14.2 mmol), 4-fluorophenol (2.39 g, 21.3 mmol), and potassium carbonate (3.92 g, 28.4 mmol) in DMF (45 mL) is stirred at 90° C. for 3 hours. After cooling to rt, the mixture is filtered through a pad of Celite and rinsed with EtOAc (200 mL). The filtrate is washed with water (200 mL) and brine (200 mL), dried over sodium sulfate, and concentrated in vacuo. The residue is purified by chromatography on silica gel eluting with n-hexane/EtOAc (20:1) to give 3.46 g (93% yield) of the title compound as a white solid.

¹H-NMR (300 MHz, CDCl₃) delta 8.59 (1H, d, J=2.2 Hz), 8.12 (1H, d, J=2.2 Hz), 7.15-7.06 (4H, m), 3.90 (3H, s), 2.40 (3H, s), MS (ESI) m/z: 262 (M+H)⁺.

<Step-2>: 6-(4-fluorophenoxy)-5-methylnicotinic acid

The title compound is prepared in 91% yield (2.98 g, a white solid) from methyl 6-(4-fluorophenoxy)-5-methylnicotinate (3.46 g, 13.2 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A6.

¹H-NMR (300 MHz, CDCl₃) delta 8.67 (1H, d, J=2.2 Hz), 8.16 (1H, d, J=2.2 Hz), 7.18-7.06 (4H, m), 2.40 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 248 (M+H)⁺.

<Step-3>: (6-(4-fluorophenoxy)-5-methylpyridin-3-yl)methanol

The title compound is prepared in 98% yield (417 mg, a white solid) from 6-(4-fluorophenoxy)-5-methylnicotinic acid (450 mg, 1.82 mmol, Step-2) in a similar manner to Step-2 of Intermediate-A3.

¹H-NMR (300 MHz, CDCl₃) delta 7.93 (1H, s), 7.59 (1H, s), 7.15-7.03 (4H, m), 4.62 (2H, d, J=5.5 Hz), 2.36 (3H, s), 1.65 (1H, t, J=5.5 Hz), MS (ESI) m/z: 234 (M+H)⁺.

Intermediate-A13 (5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methanol <Step-1>: 5-methyl-6-(3,3,3-trifluoropropoxy)nicotinic acid

To a solution of sodium hydride (0.844 g, 21.1 mmol) in THF (10 mL), 3,3,3-trifluoropropan-1-ol (1.61 g, 14.1 mmol) in THF (10 mL) is added at 0° C., and stirred for 5 minutes. Then methyl 6-fluoro-5-methylnicotinate (1.19 g, 7.04 mmol) in THF (10 mL) is added dropwise the reaction mixture and the resulting mixture is stirred at rt for 2 hours. The reaction mixture is diluted with water (30 mL) and stirred overnight. After removal of THF, the mixture is acidified with 2 M hydrochloric acid (11 mL). The resulting white precipitate is collected by filtration and dried to give 1.76 g (quantitative yield) of the title compound as a white solid. This material is used for the next reaction (Step-2) without further purification.

MS (ESI) m/z: 250 (M+H)⁺.

<Step-2>: (5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methanol

The title compound is prepared in 95% yield (2.43 g, a white solid) from 5-methyl-6-(3,3,3-trifluoropropoxy)nicotinic acid (2.71 g, 10.9 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A3.

¹H-NMR (270 MHz, CDCl₃) delta 7.94 (1H, s), 7.47 (1H, s), 4.62-4.54 (4H, m), 2.71-2.56 (2H, m), 2.19 (3H, s), 1.62 (1H, t, J=5.9 Hz), MS (ESI) m/z: 236 (M+H)⁺.

Intermediate-A14 (5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methanol <Step-1>: A mixture of 6-chloro-4-methyl-3-(2,2,2-trifluoroethoxy)pyridazine and 3-chloro-4-methyl-6-(2,2,2-trifluoroethoxy)pyridazine (2:1)

To a stirred solution of 2,2,2-trifluoroethanol (2.03 g, 20.2 mmol), DMF (20 mL) and THF (10 mL) is added 60% sodium hydride (0.78 g, 20.2 mmol) at 0° C. carefully. After stirring at rt for 1 hour, this solution is added to a solution of 3,6-dichloro-4-methylpyridazine (3.00 g, 18.4 mmol) in DMF (20 mL) at 0° C. slowly. The resulting mixture is stirred at rt for 1 hour. The mixture is poured onto ice-water, and extracted with EtOAc (200 mL). The organic layer is washed with water (200 mL×2), and dried over sodium sulfate. After removal of the organic solvent, the residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (9:1) to give 3.40 g of a mixture of the title compound (81% yield) as a white solid.

MS (ESI) m/z: 227 (M+H)⁺.

<Step-2>: ethyl 5-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate and ethyl 4-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate

A mixture of 6-chloro-4-methyl-3-(2,2,2-trifluoroethoxy)pyridazine and 3-chloro-4-methyl-6-(2,2,2-trifluoroethoxy)pyridazine (3.40 g, 15.0 mmol, Step-1), palladium(II) acetate (0.34 g, 1.50 mmol), 1,3-bis(diphenylphosphino)propane (1.24 g, 3.00 mmol), triethylamine (6.27 mL, 45.0 mmol), DMF (40 mL), and EtOH (20 mL) is stirred at 80° C. under carbon monoxide atmosphere (1 atm) for 20 hours. After cooling to rt, the mixture is diluted with EtOAc (200 mL). This is washed with water (200 mL×2), and the organic layer is dried over sodium sulfate. After removal of the organic solvent, the residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (8:1-5:1) to give 2.15 g of ethyl 5-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate (54% yield, more polar product) as an off-white solid and 0.63 g of ethyl 4-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate (16% yield, less polar product) as pale yellow oil.

ethyl 5-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate (more polar)

¹H-NMR (300 MHz, CDCl₃) delta 7.99 (1H, d, J=1.5 Hz), 5.02 (2H, q, J=8.1 Hz), 4.50 (2H, q, J=7.3 Hz), 2.36 (3H, s), 1.46 (3H, t, J=7.3 Hz), MS (ESI) m/z: 265 (M+H)⁺.

ethyl 4-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate (less polar)

¹H-NMR (300 MHz, CDCl₃) delta 7.00 (1H, s), 4.99 (2H, q, J=8.1 Hz), 4.49 (2H, q, J=7.3 Hz), 2.58 (3H, s), 1.46 (3H, t, J=7.3 Hz), MS (ESI) m/z: 265 (M+H)⁺.

<Step-3>: (5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methanol

The title compound is prepared in 30% yield (373 mg, a brown oil) from ethyl 5-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate (1.5 g, 5.7 mmol, Step-2) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, CDCl₃) delta 7.31 (1H, s), 4.93 (2H, q, J=8.1 Hz), 4.86 (2H, s), 2.31 (3H, s) (a signal due to OH is not observed), MS (ESI) m/z: 223 (M+H)⁺.

Intermediate-A15 4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol <Step-1>: 2-chloro-4-methyl-5-(2,2,2-trifluoroethoxy)pyridine

To a mixture of 6-chloro-4-methylpyridin-3-ol (2.00 g, 13.9 mmol) and cesium carbonate (6.81 g, 20.9 mmol) in DMF (40 mL) is added dropwise 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.56 g, 15.3 mmol) at 0° C. After stirring at rt for 1 hour, the mixture is poured onto water (300 mL). The aqueous layer is extracted with EtOAc (300 mL). The separated organic layer is washed with water (200 mL), dried over sodium sulfate, and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (9:1) to give 3.00 g (95% yield) of the title compound as a white solid.

¹H-NMR (300 MHz, CDCl₃) delta 7.90 (1H, s), 7.17 (1H, s), 4.43 (2H, q, J=7.3 Hz), 2.28 (3H, s), MS (ESI) m/z: 226 (M+H)⁺.

<Step-2>: ethyl 4-methyl-5-(2,2,2-trifluoroethoxy)picolinate

The title compound is prepared in 90% yield (3.14 g, a white solid) from 2-chloro-4-methyl-5-(2,2,2-trifluoroethoxy)pyridine (3.00 g, 13.3 mmol, step-1) in a similar manner to Step-2 of Intermediate-A14.

¹H-NMR (300 MHz, CDCl₃) delta 8.24 (1H, s), 8.00 (1H, s), 4.57-4.42 (4H, m), 2.35 (3H, s), 1.44 (3H, t, J=6.6 Hz), MS (ESI) m/z: 264 (M+H)⁺.

<Step-3>: (4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol

The title compound is prepared in 72% yield (913 mg, a pale yellow solid) from ethyl 4-methyl-5-(2,2,2-trifluoroethoxy)picolinate (1.50 g, 5.7 mmol, Step-2) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, CDCl₃) delta 8.09 (1H, s), 7.09 (1H, s), 4.68 (2H, d, J=3.7 Hz), 4.44 (2H, q, J=8.1 Hz), 3.44 (1H, br s), 2.30 (3H, s), MS (ESI) m/z: 222 (M+H)⁺.

Intermediate-A16 (3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)methanol <Step-1>: 3-methyl-4-(2,2,2-trifluoroethoxy)benzoic acid

To a stirred solution of 4-hydroxy-3-methylbenzoic acid (10 g, 65.7 mmol) and cesium carbonate (64.2 g, 197 mmol) in DMF (150 mL) is added 2,2,2-trifluoroethyl trifluoromethanesulfonate (33.6 g, 145 mmol) at 0° C. The mixture is stirred at 0° C. for 10 minutes then stirred at rt for 2 days. To the mixture are added water (150 mL) and NaOH pellet (15 g), and the resulting mixture is stirred for 20 hours at rt. The mixture is diluted with water (100 mL), washed with ether (100 mL×2), and the water layer is acidified with conc. hydrochloric acid (pH 4) at 0° C. to give a white solid. The solid is collected by filtration, washed successively with water and n-hexane, and dried in vacuo at 50° C. to give 14.8 g (96% yield) of the title compound as a white solid.

¹H-NMR (300 MHz, CDCl₃) delta 7.98-7.90 (2H, m), 6.83 (1H, d, J=8.0 Hz), 4.43 (2H, q, J=7.3 Hz), 2.31 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 233 (M−H)⁻.

<Step-2>: (3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)methanol

The title compound is prepared in 80% yield (5.26 g, a white solid) from 3-methyl-4-(2,2,2-trifluoroethoxy)benzoic acid (7.00 g, 29.9 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, CDCl₃) delta 7.19-7.16 (2H, m), 6.78 (1H, d, J=8.4 Hz), 4.62 (2H, d, J=5.9 Hz), 4.35 (2H, q, J=8.7 Hz), 2.27 (3H, s) (a signal due to OH is not observed), MS (ESI) m/z: positive ion of a fragment signal 203 is observed.

Intermediate-A17 (4-(2,2-difluoroethoxy)-3-methylphenyl)methanol <Step-1>: methyl 4-(2,2-difluoroethoxy)-3-methylbenzoate

To a stirred solution of methyl 4-hydroxy-3-methylbenzoate (1.5 g, 9.0 mmol), 2,2-difluoroethanol (0.90 g, 10.8 mmol), triphenylphosphine (3.6 g, 13.5 mmol) in THF (40 mL) is added dropwise diethyl azodicarboxylate (4.9 mL, 10.8 mmol, 40% solution in toluene) at 0° C. The mixture is stirred at rt for 30 minutes. Then the reaction mixture is stirred at 60° C. for 2 hours. After cooling to rt, the mixture is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (18:1) to give 1.9 g (90% yield) of the title compound as a white solid.

¹H-NMR (300 MHz, CDCl₃) delta 7.90-7.85 (2H, m), 6.79 (1H, d, J=8.8 Hz), 6.13 (1H, tt, J=54.9, 4.4 Hz), 4.24 (2H, td, J=12.5, 3.7 Hz), 3.89 (3H, s), 2.27 (3H, s).

<Step-2>: (4-(2,2-difluoroethoxy)-3-methylphenyl)methanol

The title compound is prepared in quantitative yield (712 mg, a colorless oil) from methyl 4-(2,2-difluoroethoxy)-3-methylbenzoate (750 mg, 3.3 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, CDCl₃) delta 7.18-7.15 (2H, m), 6.78 (1H, d, J=8.1 Hz), 6.11 (1H, tt, J=54.9, 4.2 Hz), 4.61 (2H, d, J=5.9 Hz), 4.19 (2H, tt, J=13.0, 4.2 Hz), 2.25 (3H, s) (a signal due to OH is not observed).

Intermediate-A18 (5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanol <Step-1>: 5-methyl-6-(2,2,3,3-tetrafluoropropoxy)nicotinic acid

The title compound is prepared in quantitative yield (3.7 g, a white solid) from 6-fluoro-5-methylnicotinic acid (2.0 g, 12.9 mmol) and 2,2,3,3-tetrafluoropropan-1-ol (3.4 g, 25.8 mmol) in a similar manner to Step-1 of Intermediate-A1.

¹H-NMR (300 MHz, CDCl₃) delta 8.74 (1H, d, J=2.2 Hz), 8.09 (1H, d, J=2.2 Hz), 6.00 (1H, tt, J=52.7, 3.7 Hz), 4.84 (2H, t, J=12.5 Hz), 2.28 (3H, s), a signal due to COOH is not observed, MS (ESI) m/z: 268 (M+H)⁺.

<Step-2>: (5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanol

The title compound is prepared in 98% yield (0.93 g, a yellow oil) from 5-methyl-6-(2,2,3,3-tetrafluoropropoxy)nicotinic acid (1.00 g, 3.74 mmol) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, DMSO-d₆) delta 7.93 (1H, s), 7.57 (1H, s), 6.68 (1H, tt, J=52.0, 5.9 Hz), 5.19 (1H, t, J=5.9 Hz), 4.84 (2H, t, J=13.9 Hz), 4.43 (2H, d, J=5.9 Hz), 2.18 (3H, s), MS (ESI) m/z: 254 (M+H)⁺.

Intermediate-A19 (2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanol <Step-1>: ethyl 2-methyl-6-(2,2,2-trifluoroethoxy)isonicotinate

The title compound is prepared in 83% yield (2.42 g, a colorless oil) from ethyl 2-hydroxy-6-methylisonicotinate (2.0 g, 11.0 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.82 g, 12.1 mmol) in a similar manner to Step-1 of Intermediate-A15.

¹H-NMR (270 MHz, CDCl₃) delta 7.36 (1H, s), 7.23 (1H, s), 4.78 (2H, q, J=8.6 Hz), 4.38 (2H, q, J=7.3 Hz), 2.50 (3H, s), 1.39 (3H, t, J=7.3 Hz), MS (ESI) m/z: 264 (M+H)⁺.

<Step-2>: (2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanol

The title compound is prepared in 90% yield (753 mg, a colorless oil) from ethyl 2-methyl-6-(2,2,2-trifluoroethoxy)isonicotinate (1.00 g, 3.8 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, CDCl₃) delta 6.80 (1H, s), 6.66 (1H, s), 4.76 (2H, d, J=8.8 Hz), 4.67 (2H, q, J=5.9 Hz), 2.43 (3H, s), 1.81 (1H, t, J=5.9 Hz), MS (ESI) m/z: 222 (M+H)⁺.

Intermediate-A20 (1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-3-yl)methanol

The title compound is prepared in 92% yield (1.04 g, colorless oil) from 1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxylic acid (1.2 g, 4.7 mmol) in a similar manner to Step-2 of Intermediate-A3.

¹H-NMR (300 MHz, CDCl₃) delta 8.66 (1H, s), 8.56 (1H, d, J=2.2 Hz), 8.08-8.00 (2H, m), 6.50 (1H, d, J=2.9 Hz), 4.81 (2H, d, J=5.8 Hz), MS (ESI) m/z: 244 (M+H)⁺.

Intermediate-A21 (6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methanol <Step-1>: 6-(cyclopropylmethoxy)-5-methylnicotinic acid

To a suspension of sodium hydride (2.04 g, 60% in oil, 53.2 mmol) in THF (30 mL), cyclopropylmethanol (3.84 g, 53.2 mmol) and methyl 6-fluoro-5-methylnicotinate (1.50 g, 8.9 mmol) are added, and the mixture is stirred at 0° C. for 1 hour. Then, 1 M aqueous sodium hydroxide solution (20 mL), EtOH (10 mL), and THF (10 mL) are added, and the mixture is stirred at 60° C. for 1 hour. After cooling to rt, the mixture is acidified by 2 M hydrochloric acid (pH 4), and the aqueous layer is extracted with EtOAc (100 mL). The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with DCM/MeOH (20:1) to give 1.72 g of the title compound (containing ca 20% of 6-methoxy-5-methylnicotinic acid) as a white solid. This is used for the next step without further purification.

MS (ESI) m/z: 206 (M−H)⁻.

<Step-2>: (6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methanol

The title compound is prepared in 68% yield (1.10 g, a white solid) from 6-(cyclopropylmethoxy)-5-methylnicotinic acid (1.72 g, 8.30 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, CDCl₃) delta, 7.92 (1H, s), 7.45 (1H, s), 4.59 (2H, d, J=5.9 Hz), 4.15 (2H, d, J=6.6 Hz), 2.22 (3H, s), 1.54 (1H, t, J=5.9 Hz), 1.35-1.24 (1H, m), 0.62-0.55 (2H, m), 0.37-0.32 (2H, m), MS (ESI) m/z: 194 (M+H)⁺.

Intermediate-A22 (2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol <Step-1>: methyl 2-methoxy-6-(2,2,2-trifluoroethoxy)nicotinate

The title compound is prepared in 54% yield (1.79 g, colorless oil) from methyl 6-chloro-2-methoxynicotinate (2.5 g, 12.4 mmol) and 2,2,2-trifluoroethanol (2.78 g, 24.8 mmol) in a similar manner to Step-1 of Intermediate-A6.

¹H-NMR (300 MHz, CDCl₃) delta 8.21 (1H, d, J=8.0 Hz), 6.47 (1H, d, J=8.0 Hz), 4.79 (2H, q, J=8.8 Hz), 4.07 (3H, s), 3.87 (3H, s), MS (ESI) m/z: 266 (M+H)⁺.

<Step-2>: (2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol

The title compound is prepared in 74% yield (1.19 g, a white solid) from methyl 2-methoxy-6-(2,2,2-trifluoroethoxy)nicotinate (1.79 g, 6.75 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, CDCl₃) delta 7.54 (1H, d, J=8.0 Hz), 6.41 (1H, d, J=8.0 Hz), 4.72 (2H, q, J=8.8 Hz), 4.59 (2H, s), 3.97 (3H, s), 2.10 (1H, br s), MS (ESI) m/z: 238 (M+H)⁺.

Intermediate-A23 (6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methanol <Step-1>: methyl 6-methyl-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylate

A mixture of methyl 5-chloro-6-methylpyrazine-2-carboxylate (3.00 g, 16.1 mmol), 2,2,2-trifluoroethanol (32.2 g, 322 mmol), and potassium carbonate (3.33 g, 24.1 mmol) in DMF (30 mL) is stirred at 60° C. for 2 hours. After cooling to rt, the mixture is filtered off, and the filtrate is diluted with EtOAc (300 mL). The organic layer is washed with water (100 mL×3), dried over sodium sulfate, and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting EtOAc to give 3.91 g (97% yield) of the title compound as a white solid.

MS (ESI) m/z: 251 (M+H)⁺.

<Step-2>: 6-methyl-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylic acid

The title compound is prepared in 66% yield (2.44 g, a white solid) from methyl 6-methyl-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylate (3.91 g, 15.6 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A6.

¹H-NMR (300 MHz, DMSO-d₆) delta 13.36 (1H, br s), 8.67 (1H, s), 5.11 (2H, q, J=8.8 Hz), 2.48 (3H, s), MS (ESI) m/z: 235 (M−H)⁻.

<Step-3>: (6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methanol

The title compound is prepared in quantitative yield (1.9 g, a white solid) from 6-methyl-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylic acid (2.0 g, 8.5 mmol, Step-2) in a similar manner to Step-2 of Intermediate-A3.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.07 (1H, s), 5.46 (1H, t, J=1.5 Hz), 5.08-4.99 (2H, m), 4.54 (2H, d, J=5.8 Hz), 2.42 (3H, s), MS (ESI) m/z: 223 (M+H)⁺

Intermediate-A24 (6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methanol <Step-1>: 6-(2,2-difluoropropoxy)-5-methylnicotinic acid

The title compound is prepared in 87% yield (2.14 g, a white solid) from methyl 6-fluoro-5-methylnicotinate (1.80 g, 10.6 mmol) and 2,2-difluoropropan-1-ol (1.13 g, 11.7 mmol) in a similar manner to Step-1 of Intermediate-A21.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.56 (1H, d, J=1.5 Hz), 8.07 (1H, d, J=1.5 Hz), 4.64 (2H, t, J=13.2 Hz), 2.22 (3H, s), 1.75 (3H, t, J=19.1 Hz) (a signal due to COOH is not observed), MS (ESI) m/z: 230 (M−H)⁻.

<Step-2>: (6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methanol

The title compound is prepared in 93% yield (1.31 g, a colorless oil) from 6-(2,2-difluoropropoxy)-5-methylnicotinic acid (1.5 g, 6.5 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A3.

¹H-NMR (300 MHz, DMSO-d₆) delta 7.91 (1H, s), 7.55 (1H, s), 5.17 (1H, t, J=5.8 Hz), 4.54 (2H, t, J=13.2 Hz), 4.41 (2H, d, J=5.8 Hz), 2.17 (3H, s), 1.73 (3H, t, J=19.1 Hz), MS (ESI) m/z: 218 (M+H)+

Intermediate-A25 (5-cyclopropyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol <Step-1>: methyl 5-cyclopropyl-6-(2,2,2-trifluoroethoxy)nicotinate

A mixture of methyl 5-bromo-6-(2,2,2-trifluoroethoxy)nicotinate (1.00 g, 3.18 mmol), cyclopropylboronic acid (821 mg, 9.6 mmol), palladium(II) acetate (36 mg, 0.16 mmol), tricyclohexylphosphine (15% toluene solution, 595 mg, 0.32 mmol), and potassium phosphate (1.69 g, 7.96 mmol) in toluene-water (10:1, 11 mL) is refluxed with stirring for 12 hours. After cooling to rt, the mixture is filtered through a pad of Celite. The filtrate is concentrated in vacuo. The residue is purified by chromatography on silica gel eluting with n-hexane/EtOAc (20:1) to give 854 mg (97% yield) of the title compound as a white solid.

¹H-NMR (300 MHz, CDCl₃) delta 8.59-8.57 (1H, m), 7.76-7.74 (1H, m), 4.90-4.79 (2H, m), 3.91 (3H, s), 2.12-2.06 (1H, m), 1.04-0.98 (2H, m), 0.78-0.74 (2H, m), MS (ESI) m/z: 276 (M+H)⁺.

<Step-2>: (5-cyclopropyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol

The title compound is prepared in 86% yield (657 mg, a white solid) from methyl 5-cyclopropyl-6-(2,2,2-trifluoroethoxy)nicotinate (850 mg, 3.09 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, CDCl₃) delta 7.88 (1H, d, J=2.2 Hz), 7.23 (1H, d, J=2.2 Hz), 4.78 (2H, q, J=8.0 Hz), 4.60 (2H, d, J=5.9), 2.13-2.04 (1H, m), 1.71 (1H, br s), 1.02-0.95 (2H, m), 0.73-0.68 (2H, m) MS (ESI) m/z: 248 (M+H)⁺.

Intermediate-A26 (6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methanol <Step-1>: methyl 6-(4-chloro-1H-pyrazol-1-yl)-5-methylnicotinate

A mixture of methyl 6-fluoro-5-methylnicotinate (800 mg, 4.73 mmol), 4-chloro-1H-pyrazole (509 mg, 4.97 mmol), and cesium carbonate (3.08 g, 9.46 mmol) in DMF (16 mL) stirred at 60° C. for 1 hour. After cooling to rt, the mixture is diluted with EtOAc (150 mL) and washed with water (100 mL×3). The organic phase is filtered through silica gel, and the filtrate is concentrated to give 1.19 g (quantitative yield) of the title compound as a white solid.

¹H-NMR (300 MHz, CDCl₃) delta 8.88 (1H, d, J=1.5 Hz), 8.43 (1H, s), 8.26 (1H, s), 7.68 (1H, s), 3.97 (3H, s), 2.68 (3H, s), MS (ESI) m/z: 252 (M+H)⁺.

<Step-2>: 6-(4-chloro-1H-pyrazol-1-yl)-5-methylnicotinic acid

The title compound is prepared in 80% yield (904 mg, a white solid) from methyl 6-(4-chloro-1H-pyrazol-1-yl)-5-methylnicotinate (1.19 g, 4.7 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A6.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.81 (1H, s), 8.69 (1H, s), 8.36 (1H, s), 7.99 (1H, s), 2.56 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 236 (M−H)⁻.

<Step-3>: (6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methanol

The title compound is prepared in 96% yield (791 mg, a white solid) from 6-(4-chloro-1H-pyrazol-1-yl)-5-methylnicotinic acid (880 mg, 3.70 mmol, Step-2) in a similar manner to Step-2 of Intermediate-A3.

¹H-NMR (300 MHz, CDCl₃) delta 8.28 (1H, br s), 8.21 (1H, s), 7.70 (1H, br s), 7.65 (1H, s), 4.76 (2H, d, J=5.3 Hz), 2.56 (3H, s), 1.93 (1H, t, J=5.3 Hz), MS (ESI) m/z: 224 (M+H)⁺.

Intermediate-A27 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer; antipode of Intermediate-A7) <Step-1>: (S)-2-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)

The title compound is prepared in 83% yield (0.79 g, colorless oil) from 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.66 g, 2.81 mmol, Step-2 of Intermediate-A7) and (S)-2-methylpropane-2-sulfinamide in a similar manner to Step-3 of Intermediate-A7.

¹H-NMR (300 MHz, CDCl₃) delta 7.93 (1H, d, J=1.84 Hz), 7.44 (1H, s), 4.76 (2H, q, J=8.4 Hz), 4.54-4.46 (1H, m), 3.32 (1H, d, J=2.6 Hz), 2.24 (3H, s), 1.51 (3H, d, J=6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 339 (M+H)⁺.

<Step-2>: 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer; antipode of Intermediate-A7)

The title compound is prepared in 88% yield (0.56 g, a white solid) from (S)-2-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (0.79 g, 2.33 mmol, Step-1) in a similar manner to Step-4 of Intermediate-A7.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.41 (2H, br s), 8.13 (1H, d, J=2.2 Hz), 7.82 (1H, d, J=1.8 Hz), 5.02 (2H, q, J=9.2 Hz), 4.44-4.37 (1H, m), 2.19 (3H, s), 1.50 (3H, d, J=7.0 Hz), MS (ESI) m/z: 235 (M+H)⁺.

Intermediate-A28 (5-methyl-6-(2-(2,2,2-trifluoroethoxy)ethoxy)pyridin-3-yl)methanol <Step-1>: 5-methyl-6-(2-(2,2,2-trifluoroethoxy)ethoxy)nicotinic acid

The title compound is prepared in 73% yield (1.95 g, a white solid) from methyl 6-fluoro-5-methylnicotinate (1.60 g, 9.46 mmol) and 2-(2,2,2-trifluoroethoxy)ethanol (1.64 g, 11.4 mmol) in a similar manner to Step-1 of Intermediate-A21.

¹H-NMR (300 MHz, DMSO-d₆) delta 12.98 (1H, br s), 8.55 (1H, s), 8.01 (1H, s), 4.52-4.49 (2H, m), 4.16 (2H, q, J=9.5 Hz), 3.98-3.95 (2H, m), 2.19 (3H, s), MS (ESI) m/z: 278 (M−H)⁻.

<Step-2>: (5-methyl-6-(2-(2,2,2-trifluoroethoxy)ethoxy)pyridin-3-yl)methanol

The title compound is prepared in 85% yield (0.97 g, colorless oil) from 5-methyl-6-(2-(2,2,2-trifluoroethoxy)ethoxy)nicotinic acid (1.2 g, 4.3 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A3.

¹H-NMR (300 MHz, DMSO-d₆) delta 7.89 (1H, s), 7.49 (1H, s), 5.12 (1H, t, J=5.8 Hz), 4.41-4.38 (4H, m), 4.13 (2H, q, J=9.5 Hz), 3.92 (2H, t, J=4.4 Hz), 2.14 (3H, s), MS (ESI) m/z: 266 (M+H)⁺.

Intermediate-A29 (5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)methanol <Step-1>: 5-methyl-6-((2,2,2-trifluoroethyl)amino)nicotinic acid

A mixture of methyl 6-fluoro-5-methylnicotinate (2.00 g, 11.8 mmol) and 2,2,2-trifluoroethanamine (9.37 g, 95 mmol) in N-methylpyrrolidone (24 mL) is stirred at 220° C. for 2.5 hours under microwave irradiation. The mixture is diluted with MeOH (30 mL), and 2 M aqueous sodium hydroxide solution (15 mL) is added to the mixture. After stirring at 50° C. for 1 hour, the mixture is acidified by 2 M hydrochloric acid, and extracted with EtOAc/hexane (100 mL×3). The combined organic layer is washed with water (100 mL), dried over sodium sulfate, and concentrated in vacuo. The residue is crystallized from diisopropyl ether to give 884 mg (32%) of the title compound as a pale pink solid.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.49 (1H, s), 7.78 (1H, s), 7.17 (1H, t, J=6.6 Hz), 4.35-4.21 (2H, m), 2.14 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 233 (M−H)⁻.

<Step-2>: (5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)methanol

The title compound is prepared in 85% yield (623 mg, a white solid) from 5-methyl-6-((2,2,2-trifluoroethyl)amino)nicotinic acid (780 mg, 3.3 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A3.

¹H-NMR (300 MHz, CDCl₃) delta 7.99 (1H, br s), 7.36 (1H, br s), 4.56 (2H, d, J=5.5 Hz), 4.46-4.30 (1H, m), 4.30-4.21 (2H, m), 2.15 (3H, s), 1.51 (1H, t, J=5.5 Hz), MS (ESI) m/z: 221 (M+H)⁺.

Intermediate-A30 (3-methyl-4-(trifluoromethoxy)phenyl)methanol <Step-1>: ethyl 3-methyl-4-(trifluoromethoxy)benzoate

The title compound is prepared in 88% yield (1.72 g, a colorless oil) from 4-bromo-2-methyl-1-(trifluoromethoxy)benzene (2.00 g, 7.84 mmol) in a similar manner to Step-2 of Intermediate-A14.

¹H-NMR (300 MHz, CDCl₃) delta 7.95-7.88 (2H, m), 7.26-7.24 (1H, m), 4.38 (2H, q, J=7.3 Hz), 2.36 (3H, s), 1.40 (3H, t, J=7.3 Hz).

<Step-2>: (3-methyl-4-(trifluoromethoxy)phenyl)methanol

The title compound is prepared in 93% yield (620 mg, a colorless oil) from ethyl 3-methyl-4-(trifluoromethoxy)benzoate (0.80 g, 3.22 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, CDCl₃) delta 7.35-7.15 (3H, m), 4.67 (2H, d, J=5.6 Hz), 2.32 (3H, s), 1.74 (1H, t, J=5.6 Hz).

Intermediate-A31 (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanol

The title compound is prepared in 87% yield (816 mg, a colorless oil) from 2-(2,2,2-trifluoroethoxy)isonicotinic acid (1.00 g, 4.5 mmol) in a similar manner to Step-2 of Intermediate-A3.

¹H-NMR (300 MHz, CDCl₃) delta 8.10 (1H, d, J=5.1 Hz), 6.95 (1H, d, J=5.1 Hz), 6.88 (1H, s), 4.77 (2H, q, J=8.6 Hz), 4.72 (2H, d, J=5.8 Hz), 1.91 (1H, t, J=5.8 Hz), MS (ESI) m/z: 208 (M+H)⁺.

Intermediate-A32 (5-phenyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol <Step-1>: methyl 5-phenyl-6-(2,2,2-trifluoroethoxy)nicotinate

A mixture of methyl 5-bromo-6-(2,2,2-trifluoroethoxy)nicotinate (2.00 g, 6.37 mmol), phenylboronic acid (932 mg, 7.64 mmol), tetrakis(triphenylphosphine)palladium(0) (368 mg, 0.32 mmol), and sodium bicarbonate (1.07 g, 12.7 mmol) in dioxane-water (10:1, 22 mL) is refluxed with stirring for 18 hours. After cooling to rt, the mixture is poured onto water (30 mL), and the aqueous layer is extracted with EtOAc (30 mL×3). The combined organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (10:1) to give 1.99 g (quantitative yield) of the title compound as a white solid.

¹H-NMR (300 MHz, CDCl₃) delta 8.78 (1H, d, J=2.2 Hz), 8.31 (1H, d, J=2.2 Hz), 7.57 (2H, d, J=6.6 Hz), 7.48-7.40 (3H, m), 4.88 (2H, q, J=8.0 Hz), 3.95 (3H, s), MS (ESI) m/z: 312 (M+H)⁺.

<Step-2>: (5-phenyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol

The title compound is prepared in 73% yield (1.26 g, a white solid) from methyl 5-phenyl-6-(2,2,2-trifluoroethoxy)nicotinate (1.90 g, 6.10 mmol) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, CDCl₃) delta 8.10 (1H, d, J=2.2 Hz), 7.76 (1H, d, J=2.2 Hz), 7.6-7.3 (5H, m), 4.83 (2H, q, J=8.1 Hz), 4.72 (2H, s), 1.81 (1H, br s), MS (ESI) m/z: 284 (M+H)⁺.

Intermediate-A33 (1-(2,2,2-trifluoroethoxy)isoquinolin-4-yl)methanol <Step-1>: methyl 1-(2,2,2-trifluoroethoxy)isoquinoline-4-carboxylate

The title compound is prepared in 88% yield (1.14 g, a white solid) from methyl 1-chloroisoquinoline-4-carboxylate (1.00 g, 4.5 mmol) in a similar manner to Step-1 of Intermediate-A10.

¹H-NMR (300 MHz, CDCl₃) delta 8.97 (1H, d, J=8.8 Hz), 8.77 (1H, s), 8.35 (1H, d, J=8.1 Hz), 7.87-7.81 (1H, m), 7.65 (1H, t, J=8.1 Hz), 5.01 (2H, q, J=8.1 Hz), 3.99 (3H, s), MS (ESI) m/z: 286 (M+H)⁺.

<Step-2>: (1-(2,2,2-trifluoroethoxy)isoquinolin-4-yl)methanol

The title compound is prepared in quantitative yield (0.88 g, a white solid) from methyl 1-(2,2,2-trifluoroethoxy)isoquinoline-4-carboxylate (0.98 g, 3.4 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, CDCl₃) delta 8.33 (1H, d, J=8.2 Hz), 8.12 (1H, d, J=8.2 Hz), 7.97 (1H, s), 7.83-7.78 (1H, m), 7.68-7.60 (1H, m), 5.02 (2H, d, J=5.9 Hz), 4.95 (2H, q, J=8.4 Hz), 1.68 (1H, t, J=5.9 Hz), MS (ESI) m/z: 258 (M+H)⁺.

Intermediate-A34 (5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methanamine <Step-1>: 2-chloro-5-(2,2-difluoroethoxy)-4-methylpyridine

The title compound is prepared in 95% yield (4.14 g, a white solid) from 6-chloro-4-methylpyridin-3-ol (3.0 g, 20.9 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (4.92 g, 23.0 mmol) in a similar manner to Step-1 of Intermediate-A15.

¹H-NMR (300 MHz, CDCl₃) delta, 7.89 (1H, s), 7.14 (1H, s), 6.11 (1H, tt, J=54.3, 4.4 Hz), 4.26 (2H, td, J=13.2, 4.4 Hz), 2.26 (3H, s), MS (ESI) m/z: 208 (M+H)⁺.

<Step-2>: ethyl 5-(2,2-difluoroethoxy)-4-methylpicolinate

The title compound is prepared in 87% yield (4.24 g, a white solid) from 2-chloro-5-(2,2-difluoroethoxy)-4-methylpyridine (4.14 g, 19.9 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A14.

¹H-NMR (300 MHz, CDCl₃) delta, 8.24 (1H, s), 7.99 (1H, s), 6.14 (1H, tt, J=55.0, 4.4 Hz), 4.49-4.32 (4H, m), 2.32 (3H, s), 1.44 (3H, t, J=6.6 Hz), MS (ESI) m/z: 246 (M+H)⁺.

<Step-3>: (5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methanol

A mixture of ethyl 5-(2,2-difluoroethoxy)-4-methylpicolinate (2.0 g, 8.2 mmol, Step-2) and calcium chloride (3.62 g, 32.6 mmol) in THF-EtOH (1:1, 60 mL) is stirred at rt for 30 minutes. Then, the mixture is cooled to 0° C., and sodium borohydride (771 mg, 20.4 mmol) is added portionwise to it. After stirring 1 day, the reaction is quenched with saturated aqueous ammonium chloride solution (200 mL), and the aqueous layer is extracted with DCM (200 mL×2). The combined organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (10:1 then EtOAc only) to give 1.61 g (97% yield) of the title compound as a white solid.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.18 (1H, s), 7.26 (1H, s), 6.41 (1H, tt, J=54.2, 3.7 Hz), 5.31 (1H, t, J=5.9 Hz), 4.47-4.37 (4H, m), 2.21 (3H, s), MS (ESI) m/z: 204 (M+H)

<Step-4>: 2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)isoindoline-1,3-dione

The title compound is prepared in 74% yield (720 mg, a white solid) from (5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methanol (594 mg, 2.92 mmol, Step-3) and phthalimide (473 mg, 3.22 mmol) in a similar manner to Step-1 of Intermediate-A17.

¹H-NMR (300 MHz, CDCl₃) delta 8.05 (1H, s), 7.91-7.86 (2H, m), 7.78-7.70 (2H, m), 7.12 (1H, s) 6.08 (1H, tt, J=54.9, 4.5 Hz), 4.93 (2H, s), 4.27-4.17 (2H, m), 2.23 (3H, s), MS (ESI) m/z: 333 (M+H)⁺.

<Step-5>: (5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methanamine

To a suspension of 2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)isoindoline-1,3-dione (720 mg, 2.17 mmol, Step-4) in MeOH (30 mL) is added hydrazine hydrate (0.32 mL, 6.50 mmol), and the mixture is stirred at 60° C. for 5 hours. After removal of the solvent, to the residue is added 1 M aqueous sodium hydroxide solution (100 mL), and the aqueous layer is extracted with DCM (100 mL), dried over sodium sulfate, filtered and concentrated to give 307 mg (70% yield) of the title compound as a colorless oil.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.19 (1H, s), 7.25 (1H, s), 6.40 (1H, tt, J=54.2, 3.6 Hz), 4.41 (td, 1H, J=14.7 Hz, 3.6 Hz), 3.69 (2H, s), 2.19 (3H, s) (a signal due to NH2 is not observed), MS (ESI) m/z: 203 (M+H)⁺.

Intermediate-A35 (1-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)methanol <Step-1>: ethyl 1-methyl-5-(trifluoromethoxy)-1H-indole-2-carboxylate

The title compound is prepared in 99% yield (1.01 g, a brown oil) from ethyl 5-(trifluoromethoxy)-1H-indole-2-carboxylate (975 mg, 3.6 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A2.

¹H-NMR (300 MHz, CDCl₃) delta 7.52 (1H, br s), 7.40-7.34 (1H, m), 7.32-7.18 (2H, m), 4.39 (2H, q, J=7.0 Hz), 4.09 (3H, s), 1.42 (3H, t, J=7.0 Hz), MS (ESI) m/z: 288 (M+H)⁺.

<Step-2>: (1-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)methanol

The title compound is prepared in quantitative yield (0.88 g, a white solid) from ethyl 1-methyl-5-(trifluoromethoxy)-1H-indole-2-carboxylate (0.96 g, 3.3 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, CDCl₃) delta 7.44 (1H, s), 7.35-7.24 (1H, m), 7.20-7.05 (1H, m), 6.47 (1H, s), 4.81 (2H, d, J=5.6 Hz), 3.82 (3H, s), 1.63 (1H, t, J=5.6 Hz), MS (ESI) m/z: 246 (M+H)⁺.

Intermediate-A36 (3-chloro-4-(2,2-difluoroethoxy)phenyl)methanol <Step-1>: methyl 3-chloro-4-(2,2-difluoroethoxy)benzoate

The title compound is prepared in 98% yield (2.0 g, a white solid) from methyl 3-chloro-4-hydroxybenzoate (1.5 g, 8.0 mmol) in a similar manner to Step-1 of Intermediate-A17.

¹H-NMR (300 MHz, CDCl₃) delta 8.09 (1H, d, J=2.2 Hz), 7.94 (1H, dd, J=8.8, 2.2 Hz), 6.94 (1H, d, J=8.0 Hz), 6.18 (1H, tt, J=54.9, 4.4 Hz), 4.30 (2H, td, J=12.5, 4.4 Hz), 3.91 (3H, s).

<Step-2>: (3-chloro-4-(2,2-difluoroethoxy)phenyl)methanol

The title compound is prepared in quantitative yield (860 mg, clear colorless oil) from methyl 3-chloro-4-(2,2-difluoroethoxy)benzoate (930 mg, 3.7 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, CDCl₃) delta 7.42 (1H, d, J=2.2 Hz), 7.22 (1H, dd, J=8.1, 2.2 Hz), 6.93 (1H, d, J=8.8 Hz), 6.15 (1H, tt, J=54.9, 4.4 Hz), 4.63 (2H, d, J=5.1 Hz), 4.24 (2H, td, J=12.8, 4.4 Hz), 1.75-1.65 (1H, m).

Intermediate-A37 5-(chloromethyl)-3-methyl-2-((2,2,2-trifluoroethoxy)methyl)pyridine hydrochloride <Step-1>: diethyl 3-methylpyridine-2,5-dicarboxylate

The title compound is prepared in 72% yield (2.05 g, a yellow oil) from 2,5-dibromo-3-methylpyridine (3.00 g, 12.0 mmol) in a similar manner to Step-2 of Intermediate-A 14.

¹H-NMR (300 MHz, CDCl₃) delta 9.10 (1H, d, J=1.5 Hz), 8.21 (1H, s), 4.52-4.39 (4H, m), 2.62 (3H, s), 1.48-1.40 (6H, m), MS (ESI) m/z: 238 (M+H)⁺.

<Step-2>: ethyl 6-(hydroxymethyl)-5-methylnicotinate

The title compound is prepared in 74% yield (1.25 g, a pale yellow solid) from diethyl 3-methylpyridine-2,5-dicarboxylate (2.05 g, 8.6 mmol) in a similar manner to Step-3 of Intermediate-A34.

¹H-NMR (300 MHz, CDCl₃) delta 9.02 (1H, s), 8.08 (1H, s), 4.74 (2H, s), 4.42 (2H, q, J=7.3 Hz), 2.28 (3H, s), 1.42 (3H, t, J=7.3 Hz), MS (ESI) m/z: 196 (M+H)⁺.

<Step-3>: ethyl 6-(chloromethyl)-5-methylnicotinate hydrochloride

To a solution of ethyl 6-(hydroxymethyl)-5-methylnicotinate (1.25 g, 6.40 mmol) in DCM (25 mL) is added thionyl chloride (0.93 mL, 12.8 mmol) at 0° C. After stirring at rt for 1 hour, the solvent is removed in vacuo to give 1.37 g (quantitative yield) of the title compound as a pale yellow solid.

MS (ESI) m/z: 214 (M+H)⁺.

<Step-4>: 5-methyl-6-((2,2,2-trifluoroethoxy)methyl)nicotinic acid

To a mixture of 2,2,2-trifluoroethanol (3.84 g, 38.4 mmol) and cesium carbonate (8.33 g, 25.6 mmol) in DMF (20 mL) is added ethyl 6-(chloromethyl)-5-methylnicotinate hydrochloride (1.37 g, 6.39 mmol). After stirring at 40° C. for 20 hours, 2 M aqueous sodium hydroxide solution (20 mL), water (20 mL), THF (20 mL), and EtOH (20 mL) are added to the mixture. After stirring at 60° C. for 3 hours, the mixture is acidified by 2 M hydrochloric acid (pH 4). The organic solvent is removed by evaporation, and the residual aqueous layer is extracted with EtOAc/hexane. The separated organic layer is washed with water, dried over sodium sulfate, and concentrated in vacuo. The residue is crystallized from hexane to give 1.06 g (66%) of the title compound as a white solid.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.85 (1H, d, J=1.5 Hz), 8.11 (1H, s), 4.84 (2H, s), 4.22-4.12 (2H, m), 2.40 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 248 (M−H)⁻.

<Step-5>: (5-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)methanol

The title compound is prepared in 86% yield (843 mg, a colorless oil) from 5-methyl-6-((2,2,2-trifluoroethoxy)methyl)nicotinic acid (1.04 g, 4.17 mmol, Step-4) in a similar manner to Step-2 of Intermediate-A3.

¹H-NMR (300 MHz, CDCl₃) delta 8.37 (1H, d, J=1.4 Hz), 7.56 (1H, d, J=1.4 Hz), 4.82 (2H, s), 4.72 (2H, s), 3.88 (2H, q, J=8.8 Hz), 2.42 (3H, s), 2.21-2.02 (1H, m), MS (ESI) m/z: 236 (M+H)⁺.

<Step-6>: 5-(chloromethyl)-3-methyl-2-((2,2,2-trifluoroethoxy)methyl)pyridine hydrochloride

The title compound is prepared in quantitative yield (830 mg, a white solid) from (5-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)methanol (693 mg, 2.95 mmol, Step-5) in a similar manner to Step-3.

¹H-NMR (300 MHz, CDCl₃) delta 8.71 (1H, s), 8.23 (1H, s), 5.28 (2H, s), 4.72 (2H, s), 4.17 (2H, q, J=8.4 Hz), 2.63 (3H, s), MS (ESI) m/z: 254 (M+H)⁺.

Intermediate-A38 2-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethanol

The title compound is prepared in 64% yield (785 mg, a colorless oil) from 2,3-difluoro-5-(trifluoromethyl)pyridine (1.00 g, 5.46 mmol) and ethane-1,2-diol (678 mg, 10.9 mmol) in a similar manner to Step-1 of Intermediate-A10.

¹H-NMR (300 MHz, CDCl₃) delta 8.22 (1H, s), 7.57 (1H, dd, J=9.5, 1.5 Hz), 4.62-4.59 (2H, m), 4.05-4.00 (2H, m), 2.49 (1H, t, J=5.9 Hz), MS (ESI) m/z: 226 (M+H)⁺.

Intermediate-A39: (5-(2,2,3,3,3-pentafluoropropoxy)pyridin-2-yl)methanol <Step-1>: 2-bromo-5-(2,2,3,3,3-pentafluoropropoxy)pyridine

The title compound is prepared in quantitative yield (2.11 g, a yellow solid) from 6-bromo-4-methylpyridin-3-ol (1.20 g, 6.90 mmol) and 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate (13.8 mmol) in a similar manner to Step-1 of Intermediate-A15.

¹H-NMR (300 MHz, CDCl₃) delta 8.13 (1H, d, J=3.4 Hz), 7.45 (1H, d, J=8.8 Hz), 7.19 (1H, dd, J=8.8, 3.4 Hz), 4.46 (2H, t, J=11.4 Hz), MS (ESI) m/z: 306 (M+H)⁺.

<Step-2>: ethyl 5-(2,2,3,3,3-pentafluoropropoxy)picolinate

The title compound is prepared in 72% yield (1.89 g, a pale orange solid) from 2-bromo-5-(2,2,3,3,3-pentafluoropropoxy)pyridine (2.11 g, 6.9 mmol) in a similar manner to Step-2 of Intermediate-A14.

¹H-NMR (300 MHz, CDCl₃) delta 8.47 (1H, d, J=2.9 Hz), 8.16 (1H, d, J=8.6 Hz), 7.34 (1H, dd, J=8.6, 2.9 Hz), 4.60-4.40 (4H, m), 1.45 (3H, t, J=7.0 Hz), MS (ESI) m/z: 300 (M+H)⁺.

<Step-3>: (5-(2,2,3,3,3-pentafluoropropoxy)pyridin-2-yl)methanol

The title compound is prepared in 80% yield (847 mg, a colorless oil) from ethyl 5-(2,2,3,3,3-pentafluoropropoxy)picolinate (1.23 g, 4.10 mmol) in a similar manner to Step-3 of Intermediate-A34.

¹H-NMR (300 MHz, CDCl₃) delta 8.31 (1H, d, J=2.6 Hz), 7.36-7.21 (2H, m), 4.74 (2H, d, J=4.9 Hz), 4.49 (2H, t, J=12.1 Hz), 3.34 (1H, t, J=4.9 Hz), MS (ESI) m/z: 258 (M+H)⁺.

Intermediate-A40 (4-(1,1,2,2-tetrafluoroethoxy)phenyl)methanol

The title compound is prepared in 82% yield (464 mg, a colorless oil) from 4-(1,1,2,2-tetrafluoroethoxy)benzoic acid (600 mg, 2.52 mmol) in a similar manner to Step-2 of Intermediate-A3.

¹H-NMR (300 MHz, CDCl₃) delta 7.39 (2H, d, J=8.4 Hz), 7.21 (2H, d, J=8.4 Hz), 5.91 (1H, tt, J=52.9, 2.9 Hz), 4.71 (2H, d, J=5.7 Hz), 1.74 (1H, t, J=5.7 Hz).

Intermediate-A41 (5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methanol <Step-1>: 2-bromo-5-(2,2,3,3-tetrafluoropropoxy)pyridine

The title compound is prepared in quantitative yield (2.25 g, a yellow solid) from 6-bromopyridin-3-ol (1.30 g, 7.47 mmol) and 2,2,3,3-tetrafluoropropan-1-ol (3.94 g, 14.9 mmol) in a similar manner to Step-1 of Intermediate-A15.

¹H-NMR (300 MHz, CDCl₃) delta 8.12 (1H, d, J=2.9 Hz), 7.44 (1H, d, J=8.8 Hz), 7.16 (1H, dd, J=8.8, 2.9 Hz), 6.03 (1H, tt, J=52.7, 4.4 Hz), 4.40 (2H, t, J=11.7 Hz), MS (ESI) m/z: 288 and 290 (M+H)⁺.

<Step-2>: ethyl 5-(2,2,3,3-tetrafluoropropoxy)picolinate

The title compound is prepared in 94% yield (2.07 g, a pale yellow solid) from 2-bromo-5-(2,2,3,3-tetrafluoropropoxy)pyridine (2.25 g, 7.81 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A14.

¹H-NMR (300 MHz, CDCl₃) delta 8.46 (1H, d, J=2.9 Hz), 8.16 (1H, d, J=8.8 Hz), 8.33 (1H, dd, J=8.8, 2.9 Hz), 6.06 (1H, tt, J=52.7, 4.4 Hz), 4.52-4.44 (4H, m), 1.45 (3H, t, J=6.6 Hz), MS (ESI) m/z: 282 (M+H)⁺.

<Step-3>: (5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methanol

The title compound is prepared in 91% yield (717 mg, a white solid) from ethyl 5-(2,2,3,3-tetrafluoropropoxy)picolinate (923 mg, 3.28 mmol, Step-2) in a similar manner to Step-3 of Intermediate-A34.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.29 (1H, s), 7.57-7.40 (2H, m), 6.70 (1H, tt, J=52.0, 5.9 Hz), 5.37 (1H, t, J=5.9 Hz), 4.68 (2H, t, J=13.9 Hz), 4.50 (2H, d, J=5.9 Hz), MS (ESI) m/z: 240 (M+H)⁺.

Intermediate-A42 (5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanol <Step-1>: 5-chloro-6-(2,2,3,3-tetrafluoropropoxy)nicotinic acid

The title compound is prepared in 97% yield (7.29 g, a pale brown solid) from 5,6-dichloronicotinic acid (5.00 g, 26.0 mmol) and 2,2,3,3-tetrafluoropropan-1-ol (5.16 g, 39.1 mmol) in a similar manner to Step-1 of Intermediate-A3.

¹H-NMR (300 MHz, CDCl₃) delta 8.77 (1H, d, J=1.5 Hz), 8.34 (1H, d, J=2.2 Hz), 6.08 (1H, tt, J=52.8, 4.5 Hz), 4.88 (2H, t, J=12.5 Hz) (a signal due to COOH is not observed), MS (ESI) m/z: 286 (M−H)⁻.

<Step-2>: (5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanol

The title compound is prepared in 96% yield (2.49 g, a white solid) from 5-chloro-6-(2,2,3,3-tetrafluoropropoxy)nicotinic acid (2.49 g, 8.66 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A3.

¹H-NMR (300 MHz, CDCl₃) delta 8.02 (1H, d, J=2.0 Hz), 7.71 (1H, d, J=2.0 Hz), 6.09 (1H, tt, J=52.9, 4.8 Hz), 4.78 (2H, tt, J=12.2, 1.5 Hz), 4.67 (2H, d, J=5.3 Hz), 1.80 (1H, t, J=5.3 Hz), MS (ESI) m/z: 274 (M+H)⁺.

Intermediate-A43 1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: 4-methyl-5-(2,2,2-trifluoroethoxy)picolinic acid

The title compound is prepared in 92% yield (2.72 g, a white solid) from ethyl 4-methyl-5-(2,2,2-trifluoroethoxy)picolinate (3.30 g, 12.5 mmol, Step-2 of Intermediate-A 15) in a similar manner to Step-2 of Intermediate-A6.

¹H-NMR (300 MHz, CDCl₃) delta 8.12 (1H, s), 8.09 (1H, s), 4.55 (2H, q, J=7.6 Hz), 2.39 (3H, s), a signal due to COOH is not observed, MS (ESI) m/z: 236 (M+H)⁺, 234 (M−H)⁻.

<Step-2>: N-methoxy-N,4-dimethyl-5-(2,2,2-trifluoroethoxy)picolinamide

The title compound is prepared in quantitative yield (1.6 g, an off-white solid) from 4-methyl-5-(2,2,2-trifluoroethoxy)picolinic acid (1.0 g, 4.3 mmol, Step-1) in a similar manner to Step-1 of Intermediate-A7.

¹H-NMR (300 MHz, CDCl₃, 1 drop of DMSO-d₆ is added) delta 8.14 (1H, s), 7.58 (1H, br s), 4.51 (2H, q, J=8.1 Hz), 3.76 (3H, s), 3.41 (3H, s), 2.32 (3H, s), MS (ESI) m/z: 279 (M+H)⁺.

<Step-3>: 4-methyl-5-(2,2,2-trifluoroethoxy)picolinaldehyde

The title compound is prepared in 95% yield (1.2 g, a pale brown solid) from N-methoxy-N,4-dimethyl-5-(2,2,2-trifluoroethoxy)picolinamide (1.6 g, 5.8 mmol, Step-2) and lithium aluminum hydride (80 mg, 2.9 mmol) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, CDCl₃) delta 9.98 (1H, s), 8.29 (1H, s), 7.85 (1H, s), 4.57 (2H, q, J=8.1 Hz), 2.36 (3H, s), MS (ESI) m/z: 220 (M+H)⁺.

<Step-4>: (R,E)-2-methyl-N-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl ene) -propane-2-sulfinamide (single enantiomer)

A mixture of 4-methyl-5-(2,2,2-trifluoroethoxy)picolinaldehyde (1.6 g, 7.3 mmol, Step-3), (R)-2-methylpropane-2-sulfinamide (1.33 g, 11.0 mmol), and titanium tetraethoxide (2.50 g, 11.0 mmol) in THF (30 mL) is refluxed with stirring for 2 hours. After cooling to 0° C., water (30 mL) and EtOAc (80 mL) are added to the mixture, and this is filtered through a pad of Celite. The filtrate is washed successively with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (4:1-2:1) to give 1.14 g (48% yield) of the title compound as a pale yellow solid.

¹H-NMR (300 MHz, CDCl₃) delta 8.62 (1H, s), 8.25 (1H, s), 7.88 (1H, s), 4.53 (2H, q, J=8.0 Hz), 2.36 (3H, s), 1.28 (9H, s), MS (ESI) m/z: 323 (M+H)⁺.

<Step-5>: (R)-2-methyl-N-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)propane-2-sulfinamide (single diastereomer)

To a solution of (R,E)-2-methyl-N-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methylene)propane-2-sulfinamide (1.1 g, 3.4 mmol, Step-4) in DCM (50 mL) is added dropwise a solution of methylmagnesium bromide in THF (0.97 M, 7.0 mL, 6.8 mmol) at −78° C. After stirring at −78° C. for 1 h, the reaction is quenched with saturated aqueous ammonium chloride solution (100 mL). The aqueous layer is extracted with DCM (100 mL×2). The combined organic layer is washed with water (100 mL), dried over sodium sulfate, and concentrated in vacuo. The residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (1:3) to give 1.09 g (94% yield) of the title compound as a colorless oil.

¹H-NMR (300 MHz, CDCl₃) delta 8.08 (1H, s), 7.12 (1H, s), 4.65 (1H, d, J=5.4 Hz), 4.54-4.46 (1H, m), 4.42 (2H, q, J=7.9 Hz), 2.28 (3H, s), 1.48 (3H, d, J=6.6 Hz), 1.25 (9H, s), MS (ESI) m/z: 337 (M−H)⁻.

<Step-6>: 1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in quantitative yield (1.1 g, a white solid) from (R)-2-methyl-N-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)propane-2-sulfinamide (1.1 g, 3.3 mmol, Step-5) in a similar manner to Step-4 of Intermediate-A7.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.42 (2H, br s), 8.38 (1H, s), 7.43 (1H, s), 4.95 (2H, q, J=8.8 Hz), 4.50-4.38 (1H, m), 2.22 (3H, s), 1.45 (3H, d, J=6.6 Hz), MS (ESI) m/z: 235 (M+H)⁺.

Intermediate-A44 (5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methanol <Step-1>: methyl 6-chloro-5-methylnicotinate

The title compound is prepared in 93% yield (2.02 g, a white solid) from 6-chloro-5-methylnicotinic acid (2.00 g, 11.7 mmol) in a similar manner to Step-2 of Intermediate-A2.

¹H-NMR (300 MHz, CDCl₃) delta 8.83 (1H, s, J=2.2 Hz), 8.16 (1H, s), 3.95 (3H, s), 2.44 (3H, s), MS (ESI) m/z: 186 (M+H)⁺.

<Step-2>: methyl 5-methyl-6-(3,3,3-trifluoropropyl)nicotinate

To a suspension of zinc powder (2.49 g, 38.1 mmol) in THF (15 mL), 1,2-dibromoethane (0.21 g, 1.1 mmol) and trimethylsilyl chloride (0.12 g, 1.1 mmol) are added. After stirring at rt for 20 minutes, 1,1,1-trifluoro-3-iodopropane (6.10 g, 27.2 mmol) is added, and the mixture is stirred at 55° C. for 1 hour to give a solution of (3,3,3-trifluoropropyl)zinc iodide in THF. To a mixture of methyl 6-chloro-5-methylnicotinate (2.02 g, 10.9 mmol, Step-1) and tetrakis(triphenylphosphine)palladium(0) (1.01 g, 0.87 mmol) in DMF (15 mL) is added the zinc reagent, and the mixture is stirred at 55° C. for 12 hours. After cooling to rt, the mixture is poured onto water (100 mL), and the aqueous layer is extracted with EtOAc (30 mL×2). The combined organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (5:1 to EtOAc only) to give 2.32 g (86% yield) of the title compound as an orange solid.

¹H-NMR (300 MHz, CDCl₃) delta 8.97 (1H, d, J=1.5 Hz), 8.05 (1H, d, J=1.5 Hz), 3.94 (3H, s), 3.10-3.04 (2H, m), 2.76-2.62 (2H, m), 2.38 (3H, s) MS (ESI) m/z: 248 (M+H)⁺.

<Step-3>: (5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methanol

The title compound is prepared in quantitative yield (1.16 g, a pale yellow solid) from methyl 5-methyl-6-(3,3,3-trifluoropropyl)nicotinate (1.30 g, 5.26 mmol, Step-2) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, CDCl₃) delta 8.31 (1H,s), 7.49 (1H, s), 4.67 (2H, d, J=5.9 Hz), 3.03-2.98 (2H, m), 2.68-2.51 (2H, m), 2.33 (4H, s), MS (ESI) m/z: 220 (M+H)⁺.

Intermediate-A45 (4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methanol <Step-1>: 2-chloro-4-methyl-5-(3,3,3-trifluoropropoxy)pyridine

The title compound is prepared in quantitative yield (3.64 g, a pale yellow solid) from 6-chloro-4-methylpyridin-3-ol (3.00 g, 20.9 mmol) and 3,3,3-trifluoropropan-1-ol (5.72 g, 50.1 mmol) in a similar manner to Step-1 of Intermediate-A17.

¹H-NMR (300 MHz, CDCl₃) delta, 7.87 (1H, s), 7.12 (1H, s), 4.27 (2H, t, J=6.6 Hz), 2.78-2.59 (2H, m), 2.22 (3H, s), MS (ESI) m/z: 240 (M+H)⁺.

<Step-2>: ethyl 4-methyl-5-(3,3,3-trifluoropropoxy)picolinate

The title compound is prepared in 93% yield (3.92 g, a pale yellow solid) from 2-chloro-4-methyl-5-(3,3,3-trifluoropropoxy)pyridine (3.64 g, 15.2 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A14.

¹H-NMR (300 MHz, CDCl₃) delta, 8.24 (1H, s), 7.97 (1H, s), 4.49-4.36 (4H, m), 2.78-2.62 (2H, m), 2.29 (3H, s), 1.44 (3H, t, J=6.6 Hz), MS (ESI) m/z: 278 (M+H)⁺.

<Step-3>: (4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methanol

The title compound is prepared in 93% yield (807 mg, a white solid) from ethyl 4-methyl-5-(3,3,3-trifluoropropoxy)picolinate (1.0 g, 3.6 mmol, Step-2) in a similar manner to Step-3 of Intermediate-A34.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.16 (1H, s), 7.26 (1H, s), 5.28 (1H, t, J=5.8 Hz), 4.45 (2H, d, J=5.8 Hz), 4.30 (2H, t, J=5.8 Hz), 2.89-2.74 (2H, m), 2.17 (3H, s), MS (ESI) m/z: 236 (M+H)⁺.

Intermediate-A46 (5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methanol <Step-1>: 5-chloro-6-(2,2-difluoropropoxy)nicotinic acid

The title compound is prepared in 85% yield (1.12 g, a colorless oil) from 5,6-dichloronicotinic acid (1.00 g, 5.21 mmol) and 2,2-difluoropropan-1-ol (0.50 g, 5.21 mmol) in a similar manner to Step-1 of Intermediate-A3.

¹H-NMR (300 MHz, CDCl₃) delta 8.77 (1H, d, J=2.2 Hz), 8.31 (1H, d, J=2.2 Hz), 4.64 (2H, t, J=11.7 Hz), 1.80 (3H, t, J=18.3 Hz) (a signal due to COOH is not observed), MS (ESI) m/z: 252 (M+H)⁺.

<Step-2>: (5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methanol

The title compound is prepared in 73% yield (689 mg, a colorless oil) from 5-chloro-6-(2,2-difluoropropoxy)nicotinic acid (1.00 g, 3.97 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A3.

¹H-NMR (300 MHz, CDCl₃) delta 8.00 (1H, s), 7.74 (1H, d, J=1.5 Hz), 4.65 (2H, t, J=5.9 Hz), 4.55 (2H, d, J=11.7 Hz), 1.78 (3H, t, J=19.1 Hz), 1.6-1.5 (1H, m), MS (ESI) m/z: 238(M+H)⁺.

Intermediate-A47 (5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methanol <Step-1>: 5-chloro-6-(3,3,3-trifluoropropoxy)nicotinic acid

¹H-NMR (300 MHz, CDCl₃) delta 8.77 (1H, d, J=2.2 Hz), 8.29 (1H, d, J=1.5 Hz), 4.72 (2H, t, J=6.6 Hz), 2.78-2.63 (2H, m) (a signal due to COOH is not observed), MS (ESI) m/z: 270 (M+H)⁺.

<Step-2>: (5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methanol

¹H-NMR (300 MHz, CDCl₃) delta 8.00 (1H, d, J=1.8 Hz), 7.72 (1H, d, J=1.8 Hz), 4.75-4.55 (4H, m), 2.76-2.56 (2H, m), 1.80 (1H, br s), MS (ESI) m/z: 256 (M+H)⁺.

Intermediate-A48 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanol

To a solution of 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (3.41 g, 14.6 mmol, Step-2 of Intermediate-A7) in MeOH (70 mL) is added sodium borohydride (1.11 g, 29.2 mmol) at 0° C., and the mixture is stirred at rt for 3 hours. Then, the reaction is quenched with water, and the mixture is filtered through a pad of Celite. The filtrate is extracted with EtOAc, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with EtOAc to give 3.39 g (99%) of the title compound as a colorless oil.

¹H-NMR (300 MHz, CDCl₃) delta 7.93 (1H, s), 7.52 (1H, s), 4.93-4.83 (1H, m), 4.76 (2H, q, J=8.8 Hz), 2.24 (3H, s), 1.49 (3H, d, J=5.9 Hz), MS (ESI) m/z: 236 (M+H)⁺.

Intermediate-A49 (4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methanamine hydrochloride <Step-1>: 2-chloro-4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridine

To a mixture of 6-chloro-4-methylpyridin-3-ol (5.00 g, 34.8 mmol) and cesium carbonate (34.0 g, 104 mmol) in DMF (140 mL) is added 1,1,2,2-tetrafluoro-3-iodopropane (16.9 g, 69.7 mmol), and the mixture is stirred at 90 deg for 19 hours. After cooling to rt, the mixture is poured into water (500 mL), and the aqueous layer is extracted with EtOAc/hexane (3:1. 500 mL). The separated organic layer is washed with water (300 mL), dried over sodium sulfate, and concentrated in vacuo. The residue is purified by chromatography on silica gel eluting with n-hexane/EtOAc (20:1-4:1) to give 7.97 g (89% yield) of the title compound as a pale yellow solid.

¹H-NMR (300 MHz, CDCl₃) delta 7.91 (1H, s), 7.16 (1H, s), 6.02 (1H, tt, J=53.1, 4.0 Hz), 4.43 (2H, t, J=11.7 Hz), 2.26 (3H, s), MS (ESI) m/z: 258 (M+H)⁺.

<Step-2>: ethyl 4-methyl-5-(2,2,3,3-tetrafluoropropoxy)picolinate

The title compound is prepared in 90% yield (5.55 g, a white solid) from 2-chloro-4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridine (5.39 g, 20.9 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A14.

¹H-NMR (300 MHz, CDCl₃) delta 8.26 (1H, s), 8.00 (1H, s), 6.04 (1H, tt, J=53.1, 4.0 Hz), 4.60-4.35 (4H, m), 2.32 (3H, s), 1.44 (3H, t, J=7.1 Hz), MS (ESI) m/z: 296 (M+H)⁺.

<Step-3>: (4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methanol

The title compound is prepared in 80% yield (1.36 g, a colorless oil) from ethyl 4-methyl-5-(2,2,3,3-tetrafluoropropoxy)picolinate (2.00 g, 6.77 mmol, Step-2) in a similar manner to Step-3 of Intermediate-A34.

¹H-NMR (300 MHz, CDCl₃) delta 8.10 (1H, s), 7.10 (1H, s), 6.05 (1H, tt, J=53.0, 4.4 Hz), 4.68 (2H, s), 4.45 (2H, t, J=11.7 Hz), 3.58 (1H, br s), 2.28 (3H, s), MS (ESI) m/z: 254 (M+H)⁺.

<Step-4>: 2-((4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)isoindoline-1,3-dione

The title compound is prepared in 82% yield (1.70 g, a white solid) from (4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methanol (1.36 g, 5.39 mmol, Step-3) and phthalimide (873 mg, 5.93 mmol) in a similar manner to Step-1 of Intermediate-A 17.

¹H-NMR (300 MHz, CDCl₃) delta 8.06 (1H, s), 7.93-7.83 (2H, m), 7.79-7.70 (2H, m), 7.14 (1H, s), 6.02 (1H, tt, J=53.1, 4.4 Hz), 4.93 (2H, s), 4.39 (2H, t, J=11.7 Hz), 2.28 (3H, s), MS (ESI) m/z: 383 (M+H)⁺.

<Step-5>: (4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methanamine hydrochloride

The title compound is prepared in >99% yield (1.35 g, a white solid) from 2-((4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)isoindoline-1,3-dione (1.70 g, 4.44 mmol, Step-4) in a similar manner to Step-5 of Intermediate-A34.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.45 (3H, br s), 8.41 (1H, s), 7.43 (1H, s), 6.74 (1H, tt, J=51.6, 5.5 Hz), 4.80 (2H, t, J=13.2 Hz), 4.15-4.03 (2H, m), 2.25 (3H, s), MS (ESI) m/z: 253 (M+H)⁺.

Intermediate-A50: (5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methanamine hydrochloride <Step-1>: 5-chloro-6-(cyclopropylmethoxy)nicotinic acid

The title compound is prepared in 98% yield (4.65 g, a white solid) from 5,6-dichloronicotinic acid (4.00 g, 20.8 mmol) and cyclopropylmethanol (2.25 g, 31.3 mmol) in a similar manner to Step-1 of Intermediate-A3.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.63 (1H, d, J=2.2 Hz), 8.22 (1H, d, J=2.2 Hz), 4.28 (2H, d, J=7.3 Hz), 1.38-1.20 (1H, m), 0.63-0.54 (2H, m), 0.42-0.34 (2H, m) (a signal due to COOH is not observed), MS (ESI) m/z: 226 (M−H)⁻.

<Step-2>: (5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methanol

The title compound is prepared in 80% yield (1.50 g, a colorless oil) from 5-chloro-6-(cyclopropylmethoxy)nicotinic acid (2.00 g, 8.79 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A3.

¹H-NMR (300 MHz, CDCl₃) delta 7.98 (1H, d, J=2.2 Hz), 7.70 (1H, d, J=2.2 Hz), 4.62 (2H, d, J=5.5 Hz), 4.22 (2H, d, J=7.0 Hz), 1.71 (1H, t, J=5.6 Hz), 1.42-1.20 (1H, m), 0.66-0.51 (2H, m), 0.47-0.33 (2H, m), MS (ESI) m/z: 214 (M+H)⁺.

<Step-3>: 2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione

The title compound is prepared in 74% yield (1.79 g, a white solid) from (5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methanol (1.50 g, 7.00 mmol, Step-2) and phthalimide (1.13 g, 7.70 mmol) in a similar manner to Step-1 of Intermediate-A17.

¹H-NMR (300 MHz, CDCl₃) delta 8.12 (1H, d, J=2.2 Hz), 7.90-7.80 (2H, m), 7.76-7.70 (3H, m), 4.76 (2H, s), 4.19 (2H, d, J=7.4 Hz), 1.35-1.24 (1H, m), 0.69-0.50 (2H, m), 0.43-0.31 (2H, m), MS (ESI) m/z: 343 (M+H)⁺.

<Step-4>: (5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methanamine hydrochloride

The title compound is prepared in 86% yield (1.12 g, a white solid) from 2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (1.79 g, 5.23 mmol, Step-3) in a similar manner to Step-5 of Intermediate-A34.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.33 (3H, br s), 8.19 (1H, d, J=1.8 Hz), 8.07 (1H, d, J=1.8 Hz), 4.20 (2H, d, J=7.3 Hz), 4.05-3.94 (2H, m), 1.32-1.20 (1H, m), 0.61-0.51 (2H, m), 0.39-0.31 (2H, m), MS (ESI) m/z: 213 (M+H)⁺.

Intermediate-A51 1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine hydrochloride (single enantiomer) (antipode of Intermediate-A43)

The title compound is prepared according to the procedure of Intermediate-A43 using (S)-2-methylpropane-2-sulfinamide instead of (R)-2-methylpropane-2-sulfinamide.

Intermediate-A52 (3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)methanamine hydrochloride <Step-1>: (3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)methanol

The title compound is prepared in 69% yield (767 mg, a colorless oil) from 3-chloro-4-(2,2,2-trifluoroethoxy)benzoic acid (1.18 g, 4.63 mmol) in a similar manner to Step-2 of Intermediate-A3.

¹H-NMR (300 MHz, CDCl₃) delta 7.43 (1H, d, J=2.2 Hz), 7.26-7.22 (1H, m), 6.97 (1H, d, J=8.1 Hz), 4.65 (2H, d, J=5.9 Hz), 4.41 (2H, q, J=8.1 Hz), 1.71 (1H, t, J=5.5 Hz).

<Step-2>: 2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)isoindoline-1,3-dione

The title compound is prepared in 77% yield (894 mg, a white solid) from (3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)methanol (760 mg, 3.16 mmol, Step-1) in a similar manner to Step-1 of Intermediate-A17.

¹H-NMR (300 MHz, CDCl₃) delta 7.89-7.73 (2H, m), 7.74-7.71 (2H, m), 7.50 (1H, d, J=2.2 Hz) 7.33 (1H, dd, J=8.1, 2.2 Hz), 6.91 (1H, d, J=8.1 Hz), 4.78 (2H, s), 4.36 (2H, q, J=8.1 Hz).

<Step-3>: (3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)methanamine hydrochloride

The title compound is prepared in 89% yield (593 mg, an off-white solid) from 2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)isoindoline-1,3-dione (890 mg, 2.41 mmol, Step-2) in a similar manner to Step-5 of Intermediate-A34.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.47 (3H, br s), 7.68 (1H, s), 7.48 (1H, d, J=8.8 Hz), 7.33 (1H, d, J=8.8 Hz), 4.91 (2H, q, J=8.8 Hz), 3.98 (2H, d, J=5.1 Hz), MS (ESI) m/z: positive ion of a fragment signal 223 is observed.

Intermediate-A53 (6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methanamine hydrochloride <Step-1>: 6-((4-fluorobenzyl)oxy)-5-methylnicotinic acid

The title compound is prepared in 69% yield (4.26 g, a white solid) from methyl 6-fluoro-5-methylnicotinate (4.00 g, 23.7 mmol) in a similar manner to Step-1 of Intermediate-A21.

¹H-NMR (300 MHz, CDCl₃DMSO-d₆) delta 8.69 (1H, d, J=2.2 Hz), 8.01 (1H, d, J=2.2 Hz), 7.45 (2H, dd, J=8.0, 5.1 Hz), 7.06 (2H, t, J=8.8 Hz), 5.43 (2H, s), 2.24 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 260 (M−H)⁻.

<Step-2>: (6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methanol

The title compound is prepared in 91% yield (1.30 g, a white solid) from 6-((4-fluorobenzyl)oxy)-5-methylnicotinic acid (1.50 g, 5.74 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A3.

¹H-NMR (300 MHz, CDCl₃) delta 7.96 (1H, d, J=1.9 Hz), 7.51-7.38 (3H, m), 7.12-7.01 (2H, m), 5.37 (2H, s), 4.60 (2H, d, J=2.2 Hz), 2.23 (3H, s), 1.68 (1H, br s), MS (ESI) m/z: 248 (M+H)⁺.

<Step-3>: 2-((6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methyl)isoindoline-1,3-dione

The title compound is prepared in 74% yield (1.46 g, a white solid) from (6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methanol (1.30 g, 5.25 mmol, Step-2) in a similar manner to Step-1 of Intermediate-A17.

¹H-NMR (300 MHz, CDCl₃) delta 8.03 (1H, d, J=2.2 Hz), 7.83-7.70 (2H, m), 7.68-7.60 (2H, m), 7.44 (1H, d, J=1.4 Hz), 7.38-7.30 (2H, m), 7.02-6.90 (2H, m), 5.26 (2H, s), 4.68 (2H, s), 2.11 (3H, s), MS (ESI) m/z: 377 (M+H)⁺.

<Step-4>: (6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methanamine hydrochloride

The title compound is prepared in 92% yield (1.01 g, a pale yellow solid) from 2-((6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methyl)isoindoline-1,3-dione (1.46 g, 3.88 mmol, Step-3) in a similar manner to Step-5 of Intermediate-A34.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.24 (3H, br s), 8.07 (1H, d, J=1.8 Hz), 7.70 (1H, d, J=1.8 Hz), 7.55-7.43 (2H, m), 7.26-7.15 (2H, m), 5.38 (2H, s), 3.99-3.90 (2H, m), 2.19 (3H, s), MS (ESI) m/z: 247 (M+H)⁺.

Intermediate-A54 (6-cyclobutoxy-5-methylpyridin-3-yl)methanamine hydrochloride <Step-1>: 6-cyclobutoxy-5-methylnicotinic acid

The title compound is prepared in 88% yield (1.18 g, a white solid) from 6-fluoro-5-methylnicotinic acid (1.00 g, 6.45 mmol) and cyclobutanol (837 mg, 11.6 mmol) in a similar manner to Step-1 of Intermediate-A1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.50 (1H, s), 7.97 (1H, s), 5.21 (1H, quintet, J=7.3 Hz), 2.48-2.35 (2H, m), 2.16 (3H, s), 2.15-1.99 (2H, m), 1.84-1.57 (2H, m) (a signal due to COOH is not observed), MS (ESI) m/z: 208 (M+H)⁺.

<Step-2>: (6-cyclobutoxy-5-methylpyridin-3-yl)methanol

The title compound is prepared in 87% yield (2.22 g, a white solid) from 6-cyclobutoxy-5-methylnicotinic acid (2.74 g, 13.2 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A3.

¹H-NMR (300 MHz, CDCl₃) delta 7.91 (1H, s), 7.43 (1H, s), 5.21 (1H, quintet, J=7.3 Hz), 4.57 (2H, d, J=5.1 Hz), 2.58-2.41 (2H, m), 2.32-2.04 (3H, m), 2.19 (3H, s), 1.91-1.58 (2H, m), MS (ESI) m/z: 194 (M+H)⁺.

<Step-3>: 2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)isoindoline-1,3-dione

The title compound is prepared in 83% yield (3.07 g, a white solid) from (6-cyclobutoxy-5-methylpyridin-3-yl)methanol (2.22 g, 11.5 mmol, Step-2) in a similar manner to Step-1 of Intermediate-A17.

¹H-NMR (300 MHz, CDCl₃) delta 8.05 (1H, d, J=1.8 Hz), 7.92-7.78 (2H, m), 7.74-7.68 (2H, m), 7.46 (1H, d, J=1.8 Hz), 5.17 (1H, quintet, J=7.3 Hz), 4.73 (2H, s), 2.49-2.36 (2H, m), 2.20-2.00 (2H, m), 2.14 (3H, s), 1.86-1.56 (2H, m), MS (ESI) m/z: 323 (M+H)⁺.

<Step-4>: (6-cyclobutoxy-5-methylpyridin-3-yl)methanamine hydrochloride

The title compound is prepared in 96% yield (2.10 g, a white solid) from 2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)isoindoline-1,3-dione (3.07 g, 9.52 mmol, Step-3) in a similar manner to Step-5 of Intermediate-A34.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.21 (3H, br s), 8.02 (1H, s), 7.65 (1H, s), 5.15 (1H, quintet, J=7.0 Hz), 4.00-3.88 (2H, m), 2.48-2.33 (2H, m), 2.14 (3H, s), 2.11-1.95 (2H, m), 1.84-1.55 (2H, m), MS (ESI) m/z: 193 (M+H)⁺.

Intermediate-A55 (5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methanamine hydrochloride <Step-1>: 2-chloro-5-(cyclopropylmethoxy)-4-methylpyridine

The title compound is prepared in 86% yield (3.57 g, a colorless oil) from 6-chloro-4-methylpyridin-3-ol (3.00 g, 20.9 mmol) and (bromomethyl)cyclopropane (3.39 g, 25.1 mmol) in a similar manner to Step-1 of Intermediate-A15.

¹H-NMR (300 MHz, CDCl₃) delta 7.84 (1H, s), 7.10 (1H, s), 3.88 (2H, d, J=6.6 Hz), 2.25 (3H, s), 1.37-1.22 (1H, m), 0.72-0.62 (2H, m), 0.43-0.33 (2H, m), MS (ESI) m/z: 198 (M+H)⁺.

<Step-2>: ethyl 5-(cyclopropylmethoxy)-4-methylpicolinate

The title compound is prepared in 52% yield (2.21 g, a white solid) from 2-chloro-5-(cyclopropylmethoxy)-4-methylpyridine (3.57 g, 18.1 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A14.

¹H-NMR (300 MHz, CDCl₃) delta 8.21 (1H, s), 7.95 (1H, s), 4.44 (2H, q, J=6.6 Hz), 3.99 (2H, d, J=6.6 Hz), 2.31 (3H, s), 1.43 (3H, t, J=6.6 Hz), 1.39-1.23 (1H, m), 0.72-0.63 (2H, m), 0.45-0.36 (2H, m), MS (ESI) m/z: 236 (M+H)⁺.

<Step-3>: (5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methanol

The title compound is prepared in 73% yield (597 mg, a colorless oil) from ethyl 5-(cyclopropylmethoxy)-4-methylpicolinate (1.00 g, 4.25 mmol, Step-2) in a similar manner to Step-3 of Intermediate-A34.

¹H-NMR (300 MHz, CDCl₃) delta 8.05 (1H, s), 7.03 (1H, s), 4.62 (2H, s), 3.90 (2H, d, J=6.6 Hz), 2.27 (3H, s), 1.35-1.20 (1H, m), 0.69-0.60 (2H, m), 0.41-0.32 (2H, m), MS (ESI) m/z: 194 (M+H)⁺.

<Step-4>: 2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)isoindoline-1,3-dione

The title compound is prepared in 77% yield (767 mg, a white solid) from (5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methanol (597 mg, 3.09 mmol, Step-3) and phthalimide (500 mg, 3.40 mmol) in a similar manner to Step-1 of Intermediate-A17.

¹H-NMR (300 MHz, CDCl₃) delta 8.03 (1H, s), 7.90-7.82 (2H, m), 7.78-7.65 (2H, m), 7.09 (1H, s), 4.91 (2H, s), 3.85 (2H, d, J=6.6 Hz), 2.22 (3H, s), 1.39-1.18 (1H, m), 0.68-0.55 (2H, m), 0.38-0.28 (2H, m), MS (ESI) m/z: 323 (M+H)⁺.

<Step-5>: (5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methanamine hydrochloride

The title compound is prepared in >99% yield (581 mg, a white solid) from 2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)isoindoline-1,3-dione (767 mg, 2.38 mmol, Step-4) in a similar manner to Step-5 of Intermediate-A34.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.39 (3H, br s), 8.27 (1H, s), 7.43 (1H, s), 4.18-4.01 (2H, m), 4.00 (2H, d, J=6.9 Hz), 2.24 (3H, s), 1.30-1.19 (1H, m), 0.64-0.53 (2H, m), 0.41-0.30 (2H, m), MS (ESI) m/z: 193 (M+H)⁺.

Intermediate-A56 (5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)methanol <Step-1>: A mixture of 6-chloro-4-methyl-3-(2,2,3,3-tetrafluoropropoxy)pyridazine and 3-chloro-4-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazine (ca 1.5:1)

The title compound is prepared in 85% yield (5.42 g, a colorless oil) from 3,6-dichloro-4-methylpyridazine (4.00 g, 24.5 mmol) and 2,2,3,3-tetrafluoropropan-1-ol (3.56 g, 27.0 mmol) in a similar manner to Step-1 of Intermediate-A 14.

MS (ESI) m/z: 259 (M+H)⁺.

<Step-2>: ethyl 5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazine-3-carboxylate

The title compound is prepared in 27% yield (1.66 g, a yellow solid) from a mixture of 6-chloro-4-methyl-3-(2,2,3,3-tetrafluoropropoxy)pyridazine and 3-chloro-4-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazine (ca 1.5:1) (5.40 g, 20.9 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A14.

¹H-NMR (300 MHz, CDCl₃) delta 7.99 (1H, s), 6.02 (1H, tt, J=53.1, 3.7 Hz), 5.04 (2H, t, J=12.5 Hz), 4.50 (2H, q, J=7.3 Hz), 2.34 (3H, s), 1.46 (3H, t, J=7.3 Hz), MS (ESI) m/z: 297 (M+H)⁺.

<Step-3>: 5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazine-3-carboxylic acid

The title compound is prepared in >99% yield (909 mg, a white solid) from a mixture of ethyl 5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazine-3-carboxylate (980 mg, 3.31 mmol, Step-2) in a similar manner to Step-2 of Intermediate-A5.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.00 (1H, s), 6.75 (1H, tt, J=51.2, 5.1 Hz), 5.01 (2H, t, J=13.1 Hz), 2.26 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 267 (M−H)⁻.

<Step-4>: (5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)methanol

The title compound is prepared in 88% yield (670 mg, a white solid) from 5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazine-3-carboxylic acid (800 mg, 2.98 mmol, Step-3) in a similar manner to Step-2 of Intermediate-A3.

¹H-NMR (300 MHz, CDCl₃) delta 7.32 (1H, s), 6.00 (1H, tt, J=52.7, 3.7 Hz), 4.91 (2H, t, J=12.4 Hz), 4.85 (2H, s), 3.62 (1H, br s), 2.28 (3H, s), MS (ESI) m/z: 255 (M+H)⁺.

Intermediate-A57 (5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methanamine hydrochloride <Step-1>: 2-chloro-5-(2,2-difluoropropoxy)-4-methylpyridine

The title compound is prepared in 98% yield (4.52 g, a pale yellow oil) from 6-chloro-4-methylpyridin-3-ol (3.00 g, 20.9 mmol) and 2,2-difluoropropyl trifluoromethanesulfonate (11.9 g, 52.2 mmol) in a similar manner to Step-1 of Intermediate-A15.

¹H-NMR (270 MHz, CDCl₃) delta 7.88 (1H, s), 7.14 (1H, s), 4.18 (2H, t, J=11.2 Hz), 2.27 (3H, s), 1.80 (3H, t, J=18.5 Hz), MS (ESI) m/z: 222 (M+H)⁺.

<Step-2>: ethyl 5-(2,2-difluoropropoxy)-4-methylpicolinate

The title compound is prepared in 92% yield (5.35 g, a pale yellow solid) from 2-chloro-5-(2,2-difluoropropoxy)-4-methylpyridine (4.99 g, 22.5 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A14.

¹H-NMR (300 MHz, CDCl₃) delta 8.23 (1H, s), 7.99 (1H, s), 4.46 (2H, q, J=7.3 Hz), 4.28 (2H, t, J=11.0 Hz), 2.33 (3H, s), 1.81 (3H, t, J=19.1 Hz), 1.44 (3H, t, J=7.3 Hz), MS (ESI) m/z: 260 (M+H)⁺.

<Step-3>: (5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methanol

The title compound is prepared in 62% yield (1.05 g, a colorless oil) from ethyl 5-(2,2-difluoropropoxy)-4-methylpicolinate (2.00 g, 7.71 mmol, Step-2) in a similar manner to Step-3 of Intermediate-A34.

¹H-NMR (300 MHz, CDCl₃) delta 8.07 (1H, s), 7.07 (1H, s), 4.68 (2H, s), 4.20 (2H, t, J=11.3 Hz), 2.28 (3H, s), 1.81 (3H, t, J=18.7 Hz) (a signal due to OH is not observed), MS (ESI) m/z: 218 (M+H)⁺.

<Step-4>: 2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)isoindoline-1,3-dione

The title compound is prepared in 34% yield (1.05 g, a white solid) from (5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methanol (1.05 g, 4.81 mmol, Step-3) and phthalimide (779 mg, 4.81 mmol) in a similar manner to Step-1 of Intermediate-A17.

¹H-NMR (300 MHz, CDCl₃) delta 8.04 (1H, s), 7.92-7.83 (2H, m), 7.79-7.70 (2H, m), 7.13 (1H, s), 4.93 (2H, s), 4.14 (2H, t, J=11.0 Hz), 2.24 (3H, s), 1.77 (3H, t, J=18.7 Hz), MS (ESI) m/z: 347 (M+H)⁺.

<Step-5>: (5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methanamine hydrochloride

The title compound is prepared in >99% yield (1.35 g, a white solid) from 2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)isoindoline-1,3-dione (1.70 g, 4.44 mmol, Step-4) in a similar manner to Step-5 of Intermediate-A34.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.33 (1H, s), 8.31 (3H, br s), 7.36 (1H, s), 4.47 (2H, t, J=12.6 Hz), 4.08 (2H, q, J=5.5 Hz), 2.23 (3H, s), 1.77 (3H, t, J=19.4 Hz), MS (ESI) m/z: 217 (M+H)⁺.

Intermediate-A58 (4-(2,2-difluoropropoxy)-3-methylphenyl)methanamine hydrochloride <Step-1>: methyl 4-(2,2-difluoropropoxy)-3-methylbenzoate

The title compound is prepared in 76% yield (2.09 g, a white solid) from methyl 4-hydroxy-3-methylbenzoate (1.86 g, 11.2 mmol) and 2,2-difluoropropyl trifluoromethanesulfonate (6.37 g, 27.9 mmol) in a similar manner to Step-1 of Intermediate-A15.

¹H-NMR (300 MHz, CDCl₃) delta 7.92-7.85 (2H, m), 6.79 (1H, d, J=8.1 Hz), 4.16 (2H, t, J=11.0 Hz), 3.89 (3H, s), 2.28 (3H, s), 1.81 (3H, t, J=19.1 Hz), MS (ESI) m/z: 245 (M+H)⁺.

<Step-2>: (4-(2,2-difluoropropoxy)-3-methylphenyl)methanol

The title compound is prepared in >99% yield (805 mg, a white solid) from methyl 4-(2,2-difluoropropoxy)-3-methylbenzoate (900 mg, 3.68 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, CDCl₃) delta 7.23-7.12 (2H, m), 6.77 (1H, d, J=8.0 Hz), 4.61 (2H, d, J=5.9 Hz), 4.11 (2H, t, J=11.0 Hz), 2.26 (3H, s), 1.80 (3H, t, J=19.1 Hz), 1.56 (1H, t, J=5.9 Hz).

<Step-3>: 2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)isoindoline-1,3-dione

The title compound is prepared in 85% yield (1.10 g, a white solid) from (4-(2,2-difluoropropoxy)-3-methylphenyl)methanol (805 mg, 3.72 mmol, Step-2) and phthalimide (603 mg, 4.10 mmol) in a similar manner to Step-1 of Intermediate-A17.

¹H-NMR (300 MHz, CDCl₃) delta 7.91-7.80 (2H, m), 7.78-7.65 (2H, m), 7.32-7.23 (2H, m), 6.71 (1H, d, J=8.8 Hz), 4.76 (2H, s), 4.06 (2H, t, J=11.4 Hz), 2.21 (3H, s), 1.76 (3H, t, J=18.7 Hz), MS (ESI) m/z: 346 (M+H)⁺.

<Step-4>: (4-(2,2-difluoropropoxy)-3-methylphenyl)methanamine hydrochloride

The title compound is prepared in >99% yield (796 mg, a white solid) from 2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)isoindoline-1,3-dione (1.10 g, 3.17 mmol, Step-3) in a similar manner to Step-5 of Intermediate-A34.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.20 (3H, br s), 7.32-7.22 (2H, m), 7.04 (1H, d, J=8.8 Hz), 4.30 (2H, t, J=12.5 Hz), 3.92 (2H, q, J=5.9 Hz), 2.18 (3H, s), 1.76 (3H, t, J=19.1 Hz), MS (ESI) m/z: 216 (M+H)⁺.

Intermediate-A59 1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethanamine hydrochloride (single enantiomer) <Step-1>: methyl 4-(2,2-difluoroethoxy)-3-methylbenzoate

To a stirred solution of methyl 4-hydroxy-3-methylbenzoate (1.5 g, 9.0 mmol), 2,2-difluoroethanol (0.90 g, 10.8 mmol), triphenylphosphine (3.6 g, 13.5 mmol) in THF (40 mL) is added dropwise diethyl azodicarboxylate (4.9 mL, 10.8 mmol, 40% solution in toluene) at 0° C. The mixture is stirred at rt for 30 minutes. Then the reaction mixture is stirred at 60° C. for 2 hours. After cooling to rt, the mixture is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (18:1) to give 1.9 g (90% yield) of the title compound as white solid.

¹H-NMR (300 MHz, CDCl₃) delta 7.90-7.85 (2H, m), 6.79 (1H, d, J=8.8 Hz), 6.13 (1H, tt, J=54.9, 4.4 Hz), 4.24 (2H, td, J=12.5, 3.7 Hz), 3.89 (3H, s), 2.27 (3H, s).

<Step-2>: 4-(2,2-difluoroethoxy)-3-methylbenzoic acid

The title compound is prepared in >99% yield (1.1 g, white solid) from methyl 4-(2,2-difluoroethoxy)-3-methylbenzoate (1.0 g, 4.3 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A6.

¹H-NMR (300 MHz, CDCl₃) delta 7.97-7.90 (2H, m), 6.83 (1H, d, J=8.1 Hz), 6.14 (1H, tt, J=54.9, 4.4 Hz), 4.26 (2H, td, J=12.5, 4.4 Hz), 2.28 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 215 (M−H)⁻.

<Step-3>: 4-(2,2-difluoroethoxy)-N-methoxy-N,3-dimethylbenzamide

The title compound is prepared in 94% yield (900 mg, clear colorless oil) from 4-(2,2-difluoroethoxy)-3-methylbenzoic acid (800 mg, 3.7 mmol, Step-2) in a similar manner to Step-1 of Intermediate-A7.

¹H-NMR (300 MHz, CDCl₃) delta 7.60-7.50 (2H, m), 6.78 (1H, d, J=8.0 Hz), 6.13 (1H, tt, J=54.9, 4.4 Hz), 4.23 (2H, td, J=12.4, 3.7 Hz), 3.56 (3H, s), 3.35 (3H, s), 2.26 (3H, s), MS (ESI) m/z: 260 (M+H)⁺.

<Step-4>: 1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethanone

The title compound is prepared in 98% yield (730 mg, pale yellow oil) from 4-(2,2-difluoroethoxy)-N-methoxy-N,3-dimethylbenzamide (900 mg, 3.4 mmol, Step-3) in a similar manner to Step-2 of Intermediate-A7.

¹H-NMR (300 MHz, CDCl₃) delta 7.84-7.80 (2H, m), 6.81 (1H, d, J=8.0 Hz), 6.14 (1H, tt, J=54.9, 3.7 Hz), 4.25 (2H, td, J=12.5, 3.7 Hz), 2.82 (3H, s), 2.28 (3H, s), MS (ESI) m/z: 215 (M+H)⁺.

<Step-5>: (R)—N-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 47% yield (520 mg, clear colorless oil) from 1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethanone (750 mg, 3.5 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-3 of Intermediate-A7.

¹H-NMR (300 MHz, CDCl₃) delta 7.14 (2H, br), 6.75 (1H, d, J=8.8 Hz), 6.10 (1H, tt, J=54.9, 4.4 Hz), 4.50-4.40 (1H, m), 4.17 (2H, td, J=13.2, 4.4 Hz), 3.33 (1H, br s), 2.24 (3H, s), 1.47 (3H, d, J=6.6 Hz), 1.23 (9H, s).

<Step-6>: 1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 96% yield (390 mg, white solid) from (R)—N-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (750 mg, 3.5 mmol, Step-5) in a similar manner to Step-4 of Intermediate-A7.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.23 (2H, br s), 7.31-7.25 (2H, m), 7.06 (1H, d, J=8.8 Hz), 6.40 (1H, tt, J=54.2, 2.9 Hz), 4.33 (2H, td, J=14.7, 3.7 Hz), 2.18 (3H, s), 1.47 (3H, d, J=6.6 Hz) (a signal due to CHNH₂ (benzylic proton) is not observed).

Intermediate-A60 1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared from 2,2-difluoropropan-1-ol instead of 2,2-difluoroethanol in a similar manner to Intermediate-A59.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.24 (3H, br s), 7.32-7.26 (2H, m), 7.03 (1H, d, J=8.4 Hz), 4.35-4.20 (3H, m), 2.18 (3H, s), 1.74 (3H, t, J=19.1 Hz), 1.45 (3H, d, J=6.6 Hz), MS (ESI) m/z: 230 (M+H)⁺.

Intermediate-A61 1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethanamine hydrochloride (single enantiomer, antipode of Intermediate-A59)

The title compound is prepared from (S)-2-methylpropane-2-sulfinamide instead of (R)-2-methylpropane-2-sulfinamide in a similar manner to Intermediate-A59.

The following intermediate compounds are commercially available or synthesized by the known procedures.

Intermediate B1: 4-chloro-1H-pyrazolo[4,3-c]pyridine Intermediate B2: 4-chloro-6-methyl-1H-pyrazolo[4,3-c]pyridine Intermediate B3: 4-chloro-7-methyl-1H-pyrazolo[4,3-c]pyridine Intermediate B4: 4-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine Intermediate B5: 4-amino-2-chloronicotinaldehyde 2,2,2-trifluoroacetic acid salt

Representative Procedure for Method A

The following preparation of Intermediate-1a represents the Method A.

Intermediate-1a 4-chloro-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine

To a solution of 4-chloro-2H-pyrazolo[4,3-c]pyridine (1.50 g, 9.77 mmol, Intermediate-B1) (5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol (2.38 g, 10.7 mmol, Intermediate-A1) and triphenylphosphine (3.84 g, 14.7 mmol) in THF (40 mL) is added 2.2M toluene solution of diethyl azodicarboxylate (5.33 mL, 11.7 mmol) at 0° C. After stirring at rt for 16 hours, the reaction mixture is diluted with EtOAc (200 mL) and washed with water (200 mL). The organic layer is dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with hexane/EtOAc (5:1-4:1) to give 1.30 g (37% yield) of the title compound as a pale yellow solid and 1.62 g (46% yield) of its regioisomer (4-chloro-1-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1H-pyrazolo[4,3-c]pyridine) as a pale yellow solid.

¹H-NMR (300 MHz, CDCl₃) delta 8.09 (1H, s), 8.06-8.04 (2H, m), 7.48-7.45 (2H, m), 5.53 (2H, s), 4.77 (2H, q, J=8.6 Hz), 2.28 (3H, s), MS (ESI) m/z: 357 (M+H)⁺.

Representative Procedure for Method B

The following preparation of Intermediate-52a represents the Method B.

Intermediate-52a 4-chloro-2-((5-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine

A mixture of 4-chloro-2H-pyrazolo[4,3-c]pyridine (457 mg, 2.97 mmol, Intermediate-B1), 5-(chloromethyl)-3-methyl-2-((2,2,2-trifluoroethoxy)methyl)pyridine (830 mg, 3.27 mmol, Intermediate-A37), and potassium carbonate (1.65 g, 11.9 mmol) in DMF (20 mL) is stirred at 60° C. for 17 hours. After cooling to rt, the mixture is poured onto water (200 mL). The aqueous layer is extracted with EtOAc (200 mL). The separated organic layer is washed with water (100 mL), dried over sodium sulfate, and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with hexane/EtOAc (3:1 to EtOAc only) to give 242 mg (22% yield) of the title compound as a white solid and 557 mg (51% yield) of its regioisomer as a white solid.

¹H-NMR (270 MHz, DMSO-d₆) delta 9.00 (1H, s), 8.47 (1H, s), 7.99 (1H, d, J=5.9 Hz), 7.65 (1H, s), 7.56 (1H, d, J=5.9 Hz), 5.74 (2H, s), 4.75 (2H, s), 4.13 (2H, q, J=10.0 Hz), 2.31 (3H, s), MS (ESI) m/z: 371 (M+H)⁺.

Representative Procedure for Method C

The following preparation of Intermediate-1a represents the Method C.

Intermediate-1a 4-chloro-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine <Step-1>: 2-chloro-3-((((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)imino)methyl)pyridin-4-amine

To a stirred solution of 4-amino-2-chloronicotinaldehyde trifluoroacetate (1.00 g, 3.70 mmol) and (5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (1.14 g, 4.43 mmol) in THF (10 mL) is added titanium tetraisopropoxide (4.33 mL, 14.8 mmol) at rt. The resulting mixture is refluxed for 2 hours. After cooling to rt, the reaction mixture is poured into a stirred solution of 2 M aqueous sodium hydroxide solution (100 mL) at rt. Then the mixture is diluted with EtOAc (100 mL) and filtered through a pad of Celite, and washed with EtOAc (100 mL). The filtrate is washed with brine (200 mL), and the organic layer is dried over sodium sulfate. Then the organic fraction is diluted with hexane (100 mL). This solution is filtered through a silica-gel-filled glass filter, and washed with hexane/EtOAc (1:1). The filtrate is concentrated under reduced pressure to give 1.29 g (97% yield) of the title compound as a pale yellow solid.

¹H-NMR (300 MHz, CDCl₃) delta 9.00 (1H, s), 7.93 (1H, s), 7.87 (1H, d, J=5.9 Hz), 7.39 (1H, s), 6.46 (1H, d, J=5.9 Hz), 4.81-4.72 (4H, m), 2.24 (3H, s) (signals due to NH2 are not observed), MS (ESI) m/z: 359 (M+H)⁺.

<Step-2>: 4-chloro-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine

A mixture of 2-chloro-3-((((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)imino)methyl)pyridin-4-amine (1.29 g, 3.59 mmol, Step-1), iodobenzene diacetate (4.63 g, 14.4 mmol), and DMF (30 mL) is stirred at 80° C. for 2 hours. After cooling to rt, the mixture is poured onto water (150 mL), and extracted with EtOAc (150 mL×2). The combined organic fraction is washed with water (200 mL), and dried over sodium sulfate. After removal of the solvent, the residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (3:1-1:1) to give 0.59 g (46% yield) of the title compound as a white solid.

¹H-NMR and MS data are identical with those showed in Method A.

Representative Procedure for Method D

The following preparation of Intermediate-1d represents the Method D.

Intermediate-1d 4-chloro-6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine

To a THF (5 mL) solution of 4-chloro-6-methyl-1H-pyrazolo[4,3-c]pyridine (0.320 g, 1.91 mmol) is added (5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol (0.507 g, 2.3 mmol) and (cyanomethylene)tributylphosphorane (0.80 mL, 3.05 mmol) at rt. The resulting mixture is stirred at 60° C. for 20 hours under nitrogen atmosphere. The reaction mixture is concentrated to dryness. The crude reaction product is purified by column chromatography of silica gel eluting with hexane/EtOAc (5:1-1:2) to give 284 mg (40% yield) of the title compound as a white solid.

¹H-NMR (300 MHz, CDCl₃) delta 8.04-8.02 (2H, m), 7.45 (1H, br s), 7.27-7.25 (1H), 5.48 (2H, s), 4.77 (2H, q, J=8.3 Hz), 2.58 (3H, s), 2.22 (3H, s), MS (ESI) m/z: 371 (M+H)⁺.

The following intermediate compounds are prepared using the Method A, B, C, or D from starting materials shown in Table 3-1 to 3-5. Spectral data of the intermediate compounds are shown in the Table 4-1 to 4-6.

Starting Starting ID Name Method material-1 material-2 Table 3-1 Intermediate-1f 4-chloro-7-methyl-2-((5-methyl-6- D Intermediate-A1 Intermediate-B3 (2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine Intermediate-1g 4-chloro-3-methyl-2-((5-methyl-6- D Intermediate-A1 Intermediate-B4 (2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine Intermediate-2a 4-chloro-2-((6-(2,2-difluoroethoxy)-5- A Intermediate-A2 Intermediate-B1 methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-3a 4-chloro-2-(1-(5-methyl-6-(2,2,2- A Intermediate-A48 Intermediate-B1 trifluoroethoxy)pyridin-3-yl)ethyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-4a 4-chloro-2-((6-(2,2,2- A (6-(2,2,2- Intermediate-B1 trifluoroethoxy)pyridin-3-yl)methyl)-2H- trifluoroethoxy)pyridin- pyrazolo[4,3-c]pyridine 3-yl)methanol Intermediate-5a 4-chloro-2-((5-chloro-6-(2,2,2- A Intermediate-A3 Intermediate-B1 trifluoroethoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-6a 4-chloro-2-((5-chloro-6-(2,2- A Intermediate-A4 Intermediate-B1 difluoroethoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-7a 4-chloro-2-((6-(2,2-difluoroethoxy)-5- A Intermediate-A8 Intermediate-B1 fluoropyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-8a 4-chloro-2-((6-(2,2,2- A (6-(2,2,2- Intermediate-B1 trifluoroethoxy)pyridazin-3-yl)methyl)- trifluoroethoxy)pyridazin- 2H-pyrazolo[4,3-c]pyridine 3-yl)methanol Intermediate-9a 4-chloro-2-((5-(2,2,2- A (5-(2,2,2- Intermediate-B1 trifluoroethoxy)pyridin-2-yl)methyl)-2H- trifluoroethoxy)pyridin- pyrazolo[4,3-c]pyridine 2-yl)methanol Intermediate-10a 4-chloro-2-((6-(3,3,3- A Intermediate-A6 Intermediate-B1 trifluoropropoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-11a 4-chloro-2-(1-(5-methyl-6-(2,2,2- C Intermediate-A7 Intermediate-B5 trifluoroethoxy)pyridin-3-yl)ethyl)-2H- pyrazolo[4,3-c]pyridine (single enantiomer) Intermediate-12a 4-chloro-2-((5-fluoro-6-(2,2,2- A Intermediate-A5 Intermediate-B1 trifluoroethoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-13a 4-chloro-2-((6-(2,2,3,3- A Intermediate-A9 Intermediate-B1 tetrafluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine Intermediate-14a 4-chloro-2-(4-(2,2,2- A (4-(2,2,2- Intermediate-B1 trifluoroethoxy)benzyl)-2H-pyrazolo- trifluoroethoxy)phenyl)- [4,3-c]pyridine methanol Intermediate-15a 4-chloro-2-((6-(2,2,3,3,3- A Intermediate-A10 Intermediate-B1 pentafluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine Intermediate-16a 4-chloro-2-(4-(trifluoromethoxy)benzyl)- A (4-(trifluoromethoxy)- Intermediate-B1 2H-pyrazolo[4,3-c]pyridine phenyl)methanol Table 3-2 Intermediate-17a 4-chloro-2-(1-(6-(2,2-difluoroethoxy)-5- C Intermediate-A11 Intermediate-B5 methylpyridin-3-yl)ethyl)-2H- pyrazolo[4,3-c]pyridine (single enantiomer) Intermediate-18a 4-chloro-2-(2-(6-(2,2,2- A 2-(6-(2,2,2- Intermediate-B1 trifluoroethoxy)pyridin-3-yl)ethyl)-2H- trifluoroethoxy)pyridin- pyrazolo[4,3-c]pyridine 3-yl)ethanol Intermediate-19a 4-chloro-2-((6-(4-fluorophenoxy)-5- A Intermediate-A12 Intermediate-B1 methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-20a 4-chloro-2-((4-methyl-6-(2,2,2- A (4-methyl-6-(2,2,2- Intermediate-B1 trifluoroethoxy)pyridin-3-yl)methyl)-2H- trifluoroethoxy)pyridin- pyrazolo[4,3-c]pyridine 3-yl)methanol Intermediate-21a 4-chloro-2-((5-methyl-6-(3,3,3- A Intermediate-A13 Intermediate-B1 trifluoropropoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-22a 4-chloro-2-((5-methyl-6-(2,2,2- A Intermediate-A14 Intermediate-B1 trifluoroethoxy)pyridazin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine Intermediate-23a 4-chloro-2-((4-methyl-5-(2,2,2- A Intermediate-A15 Intermediate-B1 trifluoroethoxy)pyridin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-24a 4-chloro-2-((5-methoxy-6-(2,2,2- A (5-methoxy-6-(2,2,2- Intermediate-B1 trifluoroethoxy)pyridin-3-yl)methyl)-2H- trifluoroethoxy)pyridin- pyrazolo[4,3-c]pyridine 3-yl)methanol Intermediate-25a 4-chloro-2-(3-methyl-4-(2,2,2- A Intermediate-A16 Intermediate-B1 trifluoroethoxy)benzyl)-2H-pyrazolo- [4,3-c]pyridine Intermediate-26a 4-chloro-2-(4-(2,2-difluoroethoxy)-3- A Intermediate-A17 Intermediate-B1 methylbenzyl)-2H-pyrazolo[4,3-c]- pyridine Intermediate-27a 4-chloro-2-((5-methyl-6-(2,2,3,3- A Intermediate-A18 Intermediate-B1 tetrafluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine Intermediate-28a 4-chloro-2-((2-methyl-6-(2,2,2- A Intermediate-A19 Intermediate-B1 trifluoroethoxy)pyridin-4-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-29a 4-chloro-2-((6-methyl-5-(2,2,2- A (6-methyl-5-(2,2,2- Intermediate-B1 trifluoroethoxy)pyridin-2-yl)methyl)-2H- trifluoroethoxy)pyridin- pyrazolo[4,3-c]pyridine 2-yl)methanol Intermediate-30a 4-chloro-2-((1-(5- A Intermediate-A20 Intermediate-B1 (trifluoromethyl)pyridin-2-yl)-1H-pyrazol- 3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine Intermediate-31a 4-chloro-2-((5-methyl-6-(2-(2,2,2- A Intermediate-A28 Intermediate-B1 trifluoroethoxy)ethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine Intermediate-32a 4-chloro-2-((2-methoxy-6-(2,2,2- A Intermediate-A22 Intermediate-B1 trifluoroethoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-33a 4-chloro-2-(2-(4- A 2-(4-(trifluoromethyl)- Intermediate-B1 (trifluoromethyl)phenoxy)ethyl)-2H- phenoxy)ethanol pyrazolo[4,3-c]pyridine Table 3-3 Intermediate-34a 4-chloro-2-((6-methyl-5-(2,2,2- A Intermediate-A23 Intermediate-B1 trifluoroethoxy)pyrazin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-35a 4-chloro-2-((6-(2,2-difluoropropoxy)-5- A Intermediate-A24 Intermediate-B1 methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-36a 4-chloro-2-(2-((3-chloro-5- A 2-((3-chloro-5- Intermediate-B1 (trifluoromethyl)pyridin-2-yl)oxy)ethyl)- (trifluoromethyl)pyridin- 2H-pyrazolo[4,3-c]pyridine 2-yl)oxy)ethanol Intermediate-37a 4-chloro-2-((5-cyclopropy1-6-(2,2,2- A Intermediate-A25 Intermediate-B1 trifluoroethoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-38a 4-chloro-2-((6-(4-chloro-1H-pyrazol-1- A Intermediate-A26 Intermediate-B1 yl)-5-methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-39a 4-chloro-2-(1-(5-methyl-6-(2,2,2- C Intermediate-A27 Intermediate-B5 trifluoroethoxy)pyridin-3-yl)ethyl)-2H- pyrazolo[4,3-c]pyridine (single enantiomer) Intermediate-40a 4-chloro-2-((5-methyl-2-phenyl-2H- A (5-methyl-2-phenyl- Intermediate-B1 1,2,3-triazol-4-yl)rnethyl)-2H- 2H-1,2,3-triazol-4- pyrazolo[4,3-c]pyridine yl)methanol Intermediate-41a 4-chloro-2-((6-(2,2,2- A (6-(2,2,2- Intermediate-B1 trifluoroethoxy)pyridin-2-yl)methyl)-2H- trifluoroethoxy)pyridin- pyrazolo[4,3-c]pyridine 2-yl)methanol Intermediate-42a 4-chloro-2-((6-(cyclopropylmethoxy)-5- A Intermediate-A21 Intermediate-B1 methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-43a 5-((4-chloro-2H-pyrazolo[4,3-c]pyridin- A Intermediate-A29 Intermediate-B1 2-yl)methyl)-3-methyl-N-(2,2,2- trifluoroethyl)pyridin-2-amine Intermediate-44a 4-chloro-2-(3-methyl-4- A Intermediate-A30 Intermediate-B1 (trifluoromethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-45a 4-chloro-2-((2-(2,2,2- A Intermediate-A31 Intermediate-B1 trifluoroethoxy)pyridin-4-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-46a 4-chloro-2-((5-phenyl-6-(2,2,2- A Intermediate-A32 Intermediate-B1 trifluoroethoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-47a 4-((4-chloro-2H-pyrazolo[4,3-c]pyridin- A Intermediate-A33 Intermediate-B1 2-yl)methyl)-1-(2,2,2- trifluoroethoxy)isoquinoline Intermediate-48a 4-chloro-2-(4-((2,2,2- A (4-((2,2,2- Intermediate-B1 trifluoroethoxy)methyl)benzyl)-2H- trifluoroethoxy)methyl)- pyrazolo[4,3-c]pyridine phenyl)methanol Intermediate-49a 4-chloro-2-((5-(2,2-difluoroethoxy)-4- C Intermediate-A34 Intermediate-B5 methylpyridin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-50a 4-chloro-2-((1-methyl-5- A Intermediate-A35 Intermediate-B1 (trifluoromethoxy)-1H-indol-2-yl)- methyl)2H-pyrazolo[4,3-c]pyridine Table 3-4 Intermediate-51a 4-chloro-2-(3-chloro-4-(2,2- A Intermediate-A36 Intermediate-B1 difluoroethoxy)benzyl)-2H-pyrazolo- [4,3-c])pyridine Intermediate-53a 4-chloro-2-(3-(trifluoromethoxy)benzyl)- B 1-(bromomethyl)-3- Intermediate-B1 2H-pyrazolo[4,3-c]pyridine (trifluoromethoxy)benzene Intermediate-54a 4-chloro-2-(2-((3-fluoro-5- A Intermediate-A38 Intermediate-B1 (trifluoromethyl)pyridin-2-yl)oxy)ethyl)- 2H-pyrazolo[4,3-c]pyridine Intermediate-55a 4-chloro-2-((5-(2,2,3,3,3- B Intermediate-A39 Intermediate-B1 pentafluoropropoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine Intermediate-56a 4-chloro-2-(4-(1,1,2,2- A Intermediate-A40 Intermediate-B1 tetrafluoroethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-57a 4-chloro-2-((5-(2,2,3,3- A Intermediate-A41 Intermediate-B1 tetrafluoropropoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine Intermediate-58a 4-chloro-2-((5-chloro-6-(2,2,3,3- A Intermediate-A42 Intermediate-B1 tetrafluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine Intermediate-59a 4-chloro-2-(3-(trifluoromethyl)benzyl)- B 1-(chloromethyl)-3- Intermediate-B1 2H-pyrazolo[4,3-c]pyridine (trifluoromethyl)benzene Intermediate-60a 4-chloro-2-(1-(4-methyl-5-(2,2,2- C Intermediate-A43 Intermediate-B5 trifluoroethoxy)pyridin-2-yl)ethyl)-2H- pyrazolo[4,3-c]pyridine (single enantiomer) Intermediate-61a 4-chloro-2-((5-methyl-6-(3,3,3- A Intermediate-A44 Intermediate-B1 trifluoropropyl)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-62a 4-chloro-2-((4-methyl-5-(3,3,3- A Intermediate-A45 Intermediate-B1 trifluoropropoxy)pyridin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-63a 4-chloro-2-((5-chloro-6-(2,2- A Intermediate-A46 Intermediate-B1 difluoropropoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-64a 4-chloro-2-((5-chloro-6-(3,3,3- A Intermediate-A47 Intermediate-B1 trifluoropropoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-65a 4-chloro-2-((1-methyl-5- B 2-(chloromethyl)-1- Intermediate-B1 (trifluoronnethyl)-1H-benzo[d]imidazol-2- methyl-5- yl)methyl)-2H-pyrazolo[4,3-c]pyridine (trifluoromethyl)-1H- benzo[d]imidazole Intermediate-66a 4-chloro-2-((4-methyl-5-(2,2,3,3- C Intermediate-A49 Intermediate-B5 tetrafluoropropoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine Intermediate-67a 4-chloro-2-((5-chloro-6- C Intermediate-A50 Intermediate-B5 (cyclopropylmethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine Table 3-5 Intermediate-68a 4-chloro-2-(1-(4-methyl-5-(2,2,2- C Intermediate-A51 Intermediate-B5 trifluoroethoxy)pyridin-2-yl)ethyl)-2H- pyrazolo[4,3-c]pyridine (single enantiomer, antipode of Intermediate-60a) Intermediate-69a 4-chloro-2-(3-chloro-4-(2,2,2- C Intermediate-A52 Intermediate-B5 trifluoroethoxy)benzyl)-2H-pyrazolo- [4,3-c]pyridine Intermediate-70a 4-chloro-2((6-(4-fluorobenzyl)oxy)-5- C Intermediate-A53 Intermediate-B5 methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-71a 4-chloro-2-((6-cyclobutoxy-5- C Intermediate-A54 Intermediate-B5 methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-72a 4-chloro-2-((5-(cyclopropylmethoxy)-4- C Intermediate-A55 Intermediate-B5 methylpyridin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-73a 4-chloro-2-((5-methyl-6-(2,2,3,3- A Intermediate-A56 Intermediate-B1 tetrafluoropropoxy)pyridazin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine Intermediate-74a 4-chloro-2-((5-(2,2-difluoropropoxy)-4- C Intermediate-A57 Intermediate-B5 methylpyridin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridine Intermediate-75a 4-chloro-2-(4-(2,2-difluoropropoxy)-3- C Intermediate-A58 Intermediate-B5 methylbenzyl)-2H-pyrazolo- [4,3-c]pyridine Intermediate-76a 4-chloro-2-(1-(4-(2,2-difluoroethoxy)-3- C Intermediate-A59 Intermediate-B5 methylphenyl)ethyl)-2H-pyrazolo- [4,3-c]pyridine (single enantiomer) Intermediate-77a 4-chloro-2-(4-(2,2-difluoroethoxy)-3,5- C (4-(2,2- Intermediate-B5 dimethylbenzyl)-2H-pyrazolo- difluoroethoxy)-3,5- [4,3-c]pyridine dimethylphenyl) methanamine Intermediate-78a 4-chloro-2-(3-(2,2-difluoroethoxy)-4- C (3-(2,2- Intermediate-B5 methylbenzyl)-2H-pyrazolo- difluoroethoxy)-4- [4,3-c]pyridine methylphenyl) methanamine Intermediate-79a 4-chloro-2-(1-(4-(2,2-difluoropropoxy)- C Intermediate-A60 Intermediate-B5 3-methylphenyl)ethyl)-2H-pyrazolo- [4,3-c]pyridine (single enantiomer) Intermediate-80a 4-chloro-2-(1-(4-(2,2-diffuoroethoxy)-3- C Intermediate-A61 Intermediate-B5 methylphenyl)ethyl)-2H-pyrazolo- [4,3-c]pyridine (single enantiomer, antipode of Intermediate-76a) Intermediate-81a 4-chloro-2-(4-(difluoromethoxy)-3- C (4-(difluoromethoxy)- Intermediate-B5 methylbenzyl)-2H-pyrazolo- 3-methylphenyl)- [4,3-c]pyridine methanamine

ID# data Table 4-1 Intermediate-1f ¹H-NMR (300 MHz, CDCl₃) δ 8.04-8.01 (2H, m), 7.83 (1H, s), 7.46 (1H, br s), 5.54 (2H, s), 4.78 (2H, q, J = 8.6 Hz), 2.53 (3H, s), 2.23 (3H, s), MS (ESI) m/z: 371 (M + H)⁺. Intermediate-1g ¹H-NMR (300 MHz, CDCl₃) δ 7.98 (1H, d, J = 5.9 Hz), 7.92 (1H, br s), 7.41 (1H, d, J = 6.6 Hz), 7.36 (1H, br s), 5.49 (2H, s), 4.74 (2H, q, J = 8.6 Hz), 2.86 (3H, s), 2.19 (3H, s), MS (ESI) m/z: 371 (M + H)⁺. Intermediate-2a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.96 (1H, s), 8.16 (1H, d, J = 1.8 Hz), 7.99 (1H, d, J = 6.2 Hz), 7.68 (1H, d, J = 1.8 Hz), 7.56 (1H, d, J = 6.2 Hz), 6.38 (1H, tt, J = 55.0, 3.7 Hz), 5.65 (2H, s), 4.57 (2H, td, J = 15.0, 3.7 Hz), 2.14 (3H, s), MS (ESI) m/z: 339 (M + H)⁺. Intermediate-3a ¹H-NMR (270 MHz, DMSO-d₆) δ 8.97 (1H, s), 8.13 (1H, d, J = 2.0 Hz), 7.97 (1H, d, J = 6.3 Hz), 7.77 (1H, s), 7.56 (1H, d, J = 6.3 Hz), 6.04 (1H, q, J = 7.3 Hz), 4.97 (2H, q, J = 9.2 Hz), 2.14 (3H, s), 1.97 (3H, d, J = 6.9 Hz), MS (ESI) m/z: 371 (M + H)⁺. Intermediate-4a ¹H-NMR (300 MHz, CDCl₃) δ 8.22 (1H, d, J = 2.2 Hz), 8.11 (1H, s), 8.05 (1H, d, J = 6.6 Hz), 7.67 (1H, dd, J = 8.0, 2.2 Hz), 7.46 (1H, d, J = 5.9 Hz), 6.90 (1H, d, J = 8.8 Hz), 5.56 (2H, s), 4.77 (2H, q, J = 8.6 Hz), MS (ESI) m/z: 343 (M+ H)⁺. Intermediate-5a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.97 (1H, s), 8.32 (1H, d, J = 2.2 Hz), 8.14 (1H, d, J = 2.2 Hz), 8.00 (1H, d, J = 5.9 Hz), 7.57 (1H, d, J = 5.9 Hz), 5.72 (2H, s), 5.08 (2H, q, J = 8.8 Hz), MS (ESI) m/z: 377 (M + H)⁺. Intermediate-6a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.96 (1H, s), 8.28 (1H, d, J = 1.8 Hz), 8.09 (1H, d, J = 2.2 Hz), 7.98 (1H, d, J = 6.2 Hz), 7.56 (1H, d, J = 6.2 Hz), 6.40 (1H, tt, J = 54.7, 3.7 Hz), 5.69 (2H, s), 4.64 (2H, td, J = 15.0, 3.7 Hz), MS (ESI) m/z: 359 (M + H)⁺. Intermediate-7a ¹H-NMR (300 MHz, CDCl₃) δ 8.23 (1H, s), 8.21 (1H, dd, J = 5.9, 1.5 Hz), 8.00 (1H, d, J = 2.2 Hz), 7.47 (1H, d, J = 6.6 Hz), 7.38 (1H, d, J = 5.1 Hz), 6.15 (1H, tt, J = 55.4, 4.4 Hz), 5.56 (2H, s), 4.61 (2H, td, J = 13.2, 4.4 Hz), MS (ESI) m/z: 343 (M + H)⁺. Intermediate-8a ¹H-NMR (300 MHz, DMSO-d₆) δ 9.02 (1H, s), 7.99 (1H, d, J = 6.2 Hz), 7.74 (1H, d, J = 8.8 Hz), 7.55 (1H, d, J = 6.2 Hz), 7.44 (1H, d, J = 8.8 Hz), 5.99 (2H, s), 5.16 (2H, q, J = 8.8 Hz), MS (ESI) m/z: 344 (M + H)⁺. Intermediate-9a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.94 (1H, s), 8.33 (1H, d, J = 2.9 Hz), 7.98 (1H, dd, J = 6.2, 0.7 Hz), 7.57-7.51 (2H, m), 7.41 (1H, d, J = 8.8 Hz), 5.77 (2H, s), 4.86 (2H, q, J = 8.8 Hz), MS (ESI) m/z: 343 (M + H)⁺. Intermediate-10a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.96 (1H, s), 8.31 (1H, d, J = 1.8 Hz), 7.97 (1H, d, J = 6.2 Hz), 7.78 (1H, dd, J = 8.4, 2.6 Hz), 7.55 (1H, dd, J = 6.2, 1.1 Hz), 6.82 (1H, d, J = 8.4 Hz), 5.66 (2H, s), 4.46 (2H, t, J = 5.8 Hz), 2.85-2.66 (2H, m), MS (ESI) m/z: 357 (M + H)⁺. Intermediate-11a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.99 (1H, s), 8.15 (1H, d, J = 2.2 Hz), 7.99 (1H, d, J = 5.9 Hz), 7.78 (1H, d, J = 2.2 Hz), 7.58 (1H, d, J = 5.9 Hz), 6.05 (1H, q, J = 7.3 Hz), 4.99 (2H, q, J = 8.8 Hz), 2.15 (3H, s), 1.98 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 371 (M + H)⁺. Intermediate-12a ¹H-NMR (300 MHz, CDCl₃) δ 8.17 (1H, s), 8.06 (1H, dd, J = 6.6, 1.5 Hz), 8.00 (1H, br s), 7.47-7.44 (2H, m), 5.57 (2H, s), 4.84 (2H, q, J = 8.3 Hz), MS (ESI) m/z: 361 (M + H)⁺. Intermediate-13a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.96 (1H, s), 8.33 (1H, d, J = 2.2 Hz), 7.98 (1H, d, J = 6.2 Hz), 7.84 (1H, dd, J = 8.4, 2.2 Hz), 7.55 (1H, d, J = 6.2 Hz), 6.95 (1H, d, J = 8.4 Hz), 6.64 (1H, tt, J = 52.1, 5.5 Hz), 5.69 (2H, s), 4.84 (2H, t, J = 14.3 Hz), MS (ESI) m/z: 375 (M + H)⁺. Table 4-2 Intermediate-14a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.93 (1H, s), 7.97 (1H, d, J = 6.2 Hz), 7.55 (1H, d, J = 6.2 Hz), 7.40 (2H, d, J = 8.8 Hz), 7.04 (2H, d, J = 8.8 Hz), 5.63 (2H, s), 4.73 (2H, q, J = 8.8 Hz), MS (ESI) m/z: 342 (M + H)⁺. Intermediate-15a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.99 (1H, s), 8.36 (1H, d, J = 1.8 Hz), 7.99 (1H, d, J = 6.2 Hz), 7.87 (1H, dd, J = 8.4, 2.2 Hz), 7.57 (1H, dd, J = 6.2, 1.1 Hz), 6.99 (1H, d, J = 8.8 Hz), 5.71 (2H, s), 5.09 (2H, t, J = 13.9 Hz), MS (ESI) m/z: 393 (M +H)⁺. Intermediate-16a ¹H-NMR (300 MHz, DMSO-d₆) δ 9.01 (1H, s), 8.00 (1H, d, J = 6.2 Hz), 7.59-7.50 (3H, m), 7.38 (2H, d, J = 7.7 Hz), 5.76 (2H, s), MS (ESI) m/z: 328 (M + H)⁺. Intermediate-17a ¹H-NMR (300 MHz, CDCl₃) δ 8.11 (1H, s), 8.03 (1H, d, J = 6.2 Hz), 8.00 (1H, d, J = 2.2 Hz), 7.46 (1H, d, J = 6.2 Hz), 7.42 (1H, d, J = 2.2 Hz), 6.12 (1H, tt, J = 55.8, 4.4 Hz), 5.76 (1H, q, J = 7.0 Hz), 4.54 (2H, td, J = 13.6, 4.4 Hz), 2.20 (3H, s), 2.05 (3H, d, J = 7.0 Hz), MS (ESI) m/z: 353 (M + H)⁺. Intermediate-18a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.71 (1H, s), 7.98 (1H, d, J = 6.2 Hz), 7.92 (1H, d, J = 2.2 Hz), 7.61-7.56 (2H, m), 6.88 (1H, d, J = 8.4 Hz), 4.90 (2H, q, J = 8.8 Hz), 4.73 (2H, t, J = 7.0 Hz), 3.26 (2H, t, J = 7.0 Hz), MS (ESI) m/z: 357 (M + H)⁺. Intermediate-19a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.96 (1H, s), 8.06 (1H, d, J = 2.2 Hz), 7.99 (1H, d, J = 6.2 Hz), 7.77 (1H, d, J = 2.2 Hz), 7.57 (1H, d, J = 6.2 Hz), 7.25-7.11 (4H, m), 5.65 (2H, s), 2.28 (3H, s), MS (ESI) m/z: 369 (M + H)⁺. Intermediate-20a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.89 (1H, s), 8.18 (1H, s), 7.96 (1H, d, J = 6.2 Hz), 7.54 (1H, d, J = 6.2 Hz), 6.86 (1H, s), 5.72 (2H, s), 4.95 (2H, q, J = 8.8 Hz), 2.29 (3H, s), MS (ESI) m/z: 357 (M + H)⁺. Intermediate-21a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.96 (1H, s), 8.15 (1H, d, J = 1.8 Hz), 7.99 (1H, d, J = 6.2 Hz), 7.65 (1H, d, J = 1.8 Hz), 7.57 (1H, d, J = 6.2 Hz), 5.63 (2H, s), 4.49 (2H, t, J = 5.9 Hz), 2.85-2.69 (2H, m), 2.10 (3H, s), MS (ESI) m/z: 371 (M + H)⁺. Intermediate-22a ¹H-NMR (300 MHz, DMSO-d₆) δ 9.01 (1H, s), 8.00 (1H, d, J = 6.2 Hz), 7.61 (1H, s), 7.56 (1H, d, J = 6.2 Hz), 5.94 (2H, s), 5.17 (2H, q, J = 8.8 Hz), 2.20 (3H, s), MS (ESI) m/z: 358 (M + H)⁺. Intermediate-23a ¹H-NMR (270 MHz, DMSO-d₆) δ 8.93 (1H, s), 8.29 (1H, s), 7.98 (1H, d, J = 5.9 Hz), 7.54 (1H, d, J = 5.9 Hz), 7.31 (1 H, s), 5.73 (2H, s), 4.89 (2H, q, J = 8.6 Hz), 2.20 (3H, s), MS (ESI) m/z: 357 (M + H)⁺. Intermediate-24a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.96 (1H, s), 7.99 (1H, d, J = 6.2 Hz), 7.85 (1H, s), 7.58-7.53 (2H, m), 5.68 (2H, s), 4.98 (2H, q, J = 9.2 Hz), 3.81 (3H, s), MS (ESI) m/z: 373 (M + H)⁺. Intermediate-25a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.93 (1H, s), 7.98 (1H, d, J = 5.9 Hz), 7.56 (1H, d, J = 6.2 Hz), 7.29-7.26 (2H, m), 7.09-7.02 (1H, m), 5.60 (2H, s), 4.74 (2H, q, J = 8.8 Hz), 2.15 (3H, s), MS (ESI) m/z: 356 (M + H)⁺. Intermediate-26a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.90 (1H, s), 7.96 (1H, d, J = 6.2 Hz), 7.54 (1H, d, J = 5.7 Hz) 7.26 (1H, s), 7.24 (1H, d, J = 6.2 Hz), 6.98 (1H, d, J = 8.8 Hz), 6.36 (1H, tt, J = 54.7, 3.6 Hz), 5.57 (2H, s), 4.28 (2H, td, J = 14.7, 3.6 Hz), 2.13 (3H, s), MS (ESI) m/z: 338 (M + H)⁺. Intermediate-27a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.96 (1H, s), 8.17 (1H, d, J = 2.2 Hz), 7.99 (1H, d, J = 5.9 Hz), 7.71 (1H, d, J = 2.2 Hz), 7.56 (1H, d, J = 5.9 Hz), 6.67 (1H, tt, J = 52.1, 5.9 Hz), 5.66 (2H, s), 4.85 (2H, t, J = 13.2 Hz), 2.15 (3H, s), MS (ESI) m/z: 389 (M + H)⁺. Intermediate-28a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.99 (1H, s), 8.00 (1H, dd, J = 6.2, 0.7 Hz), 7.57 (1H, d, J = 6.2 Hz), 6.84 (1H, s), 6.65 (1H, s), 5.70 (2H, s), 4.94 (2H, q, J = 8.8 Hz), 2.35 (3H, s), MS (ESI) m/z: 357 (M + H)⁺. Table 4-3 Intermediate-29a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.99 (1H, s), 8.19 (1H, d, J = 5.9 Hz), 7.81 (1H, d, J = 5.9 Hz), 7.43 (1H, d, J = 8.1 Hz), 7.00 (1H, d, J = 8.1 Hz), 5.72 (2H, s), 4.79 (2H, q, J = 8.8 Hz), 2.31 (3H, s), MS (ESI) m/z: 357 (M + H)⁺. Intermediate-30a ¹H-NMR (300 MHz, DMSO-d₆) δ 9.00 (1H, s), 8.89 (1H, s), 8.66 (1H, d, J = 2.2 Hz), 8.39(1H, dd, J = 8.8 and 2.2 Hz), 8.05 (1H, d, J = 8.8 Hz), 8.00 (1H, d, J = 6.6 Hz), 7.58 (1H, d, J = 6.6 Hz), 6.66 (1 H, d, J = 2.2 Hz), 5.85 (2H, s), MS (ESI) m/z: 379 (M + H)⁺. Intermediate-31a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.95 (1H, s), 8.14 (1H, d, J = 2.2 Hz), 7.98 (1H, d, J = 6.6 Hz), 7.63 (1H, d, J = 1.5 Hz), 7.57 (1H, d, J = 6.6 Hz), 5.63 (2H, s), 4.44-4.37 (2H, m), 4.14 (2H, q, J = 8.8 Hz), 3.95-3.90 (2H, m), 2.12 (3H, s), MS (ESI) m/z: 401 (M + H)⁺. Intermediate-32a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.82 (1H, s), 7.98 (1H, d, J = 6.6 Hz), 7.70 (1H, d, J = 8.1 Hz), 7.55 (1H, d, J = 6.6 Hz), 6.55 (1H, d, J = 8.1 Hz), 5.76 (2H, s), 5.00 (2H, q, J = 8.8 Hz), 3.91 (3H, s), MS (ESI) m/z: 373 (M + H)⁺. Intermediate-33a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.90 (1H, s), 7.98 (1H, d, J = 6.2 Hz), 7.66-7.53 (3H, m), 7.09 (2H, d, J = 8.8 Hz), 4.91 (2H, t, J = 5.1 Hz), 4.63 (2H, t, J = 5.1 Hz), MS (ESI) m/z: 342 (M + H)⁺. Intermediate-34a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.97 (1H, s), 8.25 (1H, s), 7.99 (1H, d, J = 5.9 Hz), 7.55 (1H, d, J = 5.9 Hz), 5.79 (2H, s), 5.05 (2H, q, J = 8.8 Hz), 2.39 (3H, s), MS (ESI) m/z: 358 (M + H)⁺. Intermediate-35a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.96 (1H, s), 8.15 (1H, d, J = 1.5 Hz), 7.99 (1H, d, J = 6.6 Hz), 7.68 (1H, d, J = 1.5 Hz), 7.56 (1H, d, J = 6.6 Hz), 5.65 (2H, s), 4.55 (2H, t, J = 13.2 Hz), 2.15 (3H, s), 1.72 (3H, t, J = 19.1 Hz), MS (ESI) m/z: 353 (M + H)⁺. Intermediate-36a ¹H-NMR (270 MHz, CDCl₃) δ 8.34 (1H, s), 8.29 (1H, s), 8.04 (1H, d, J = 5.9 Hz), 7.87(1H, d, J = 2.2 Hz), 7.45 (1H, d, J = 7.3 Hz), 4.35-4.09 (4H, m), MS (ESI) m/z: 378 (M + H)⁺. Intermediate-37a ¹H-NMR (300 MHz, CDCl₃) δ 8.07 (1H, d, J = 2.9 Hz), 8.04 (1H, s), 8.00 (1H, d, J = 2.2 Hz), 7.46 (1H, d, J = 6.6 Hz), 7.21 (1H, d, J = 2.2 Hz), 5.50 (2H, s), 4.79 (2H, q, J = 8.8 Hz), 2.10-2.01 (1H, m), 1.01-0.96 (2H, m), 0.70-0.65 (2H, m), MS (ESI) m/z: 383 (M + H)⁺. Intermediate-38a ¹H-NMR (300 MHz, DMSO-d₆) δ 9.02 (1H, s), 8.54 (1H, s), 8.47 (1H, s), 7.99 (1H, d, J = 6.2 Hz), 7.93 (1H, s), 7.90 (1H, s), 7.57 (1H, d, J = 6.2 Hz), 5.80 (2H, s), 2.41 (3H, s), MS (ESI) m/z: 360 (M + H)⁺. Intermediate-39a ¹H-NMR (300 MHz, CDCl₃) δ 8.12 (1H, s), 8.07-8.00 (2H, m), 7.50-7.43 (2H, m), 5.77 (1H, q, J = 8.8 Hz), 4.75 (2H, q, J = 8.8 Hz), 2.22 (3H, s), 2.06 (3H, d, J = 8.8 Hz), MS (ESI) m/z: 371 (M + H)⁺. Intermediate-40a ¹H-NMR (300 MHz, DMSO-d₆) δ 9.02 (1H, s), 8.00 (1H, d, J = 5.9 Hz), 7.93 (2H, d, J = 8.8 Hz), 7.58-7.51 (3H, m), 7.40 (1H, t, J = 7.3 Hz), 5.93 (2H, s), 2.35 (3H, s), MS (ESI) m/z: 325 (M + H)⁺. Intermediate-41a ¹H-NMR (300 MHz, DMSO-d₆) δ 9.00 (1H, s), 8.01 (1H, d, J = 5.9 Hz), 7.82 (1H, t, J = 7.3 Hz), 7.57 (1H, d, J = 5.9 Hz), 6.99 (1H, d, J = 7.3 Hz), 6.94 (1H, d, J = 8.1 Hz), 5.77 (2H, s), 4.91(2H, q, J = 9.5 Hz), MS (ESI) m/z: 343 (M + H)⁺. Intermediate-42a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.94 (1H, s), 8.11 (1H, d, J = 2.2 Hz), 7.98 (1H, d, J = 5.9 Hz), 7.60 (1H, d, J = 2.2 Hz), 7.56 (1H, d, J = 5.9 Hz), 5.61 (2H, s), 4.10 (2H, d, J = 7.3 Hz), 2.11 (3H, s), 1.30-1.14 (1H, m), 0.55-0.48 (2H, m), 0.33-0.28 (2H, m), MS (ESI) m/z: 329 (M + H)⁺. Table 4-4 Intermediate-43a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.91 (1H, s), 8.07 (1H, br s), 7.98 (1H, d, J = 6.2 Hz), 7.56 (1H, d, J = 6.2 Hz), 7.42 (1H, br s), 6.63 (1H, t, J = 6.8 Hz), 5.53 (2H, s), 4.25- 4.11 (2H, m), 2.06(3H, s), MS (ESI) m/z: 356 (M + H)⁺. Intermediate-44a ¹H-NMR (300 MHz, DMSO-d₆) δ 9.00 (1H, s), 8.00 (1H, d, J = 6.2 Hz), 7.58 (1H, d, J = 6.2 Hz), 7.43 (1H, s), 7.32 (2H, s), 5.70 (2H, s), 2.26 (3H, s), MS (ESI) m/z: 342 (M + H)⁺. Intermediate-45a ¹H-NMR (300 MHz, DMSO-d₆) δ 9.03 (1H, s), 8.17 (1H, d, J =5.1 Hz), 8.01 (1H, dd, J = 6.2, 1.1 Hz), 7.59 (1H, d, J = 6.2 Hz), 6.99 (1H, d, J = 5.1 Hz), 6.86 (1H, s), 5.78 (2H, s), 4.98 (2H, q, J = 9.0 Hz), MS (ESI) m/z: 343 (M + H)⁺. Intermediate-46a ¹H-NMR (300 MHz, CDCl₃) δ 9.00 (2H, s), 8.33 (1H, s), 8.01 (1H, s), 7.59-7.38 (6H, m), 5.75 (2H, s), 5.02 (2H, q, J = 9.5 Hz), MS (ESI) m/z: 419 (M + H)⁺. Intermediate-47a ¹H-NMR (300 MHz, DMSO-d₆) δ 9.02 (1H, s), 8.30-8.20 (3H, m), 7.96 (1H, d, J = 6.2 Hz), 7.89 (1H, t, J = 8.0 Hz), 7.73 (1H, t, J = 8.0 Hz), 7.55 (1H, d, J = 6.2 Hz), 6.12 (2H, s), 5.25 (2H, q, J = 9.0 Hz), MS (ESI) m/z: 393 (M + H)⁺. Intermediate-48a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.91 (1H, s), 7.97 (1H, d, J = 6.6 Hz), 7.54 (1H, d, J = 6.6 Hz), 7.4-7.2 (4H, m), 5.70 (2H, s), 4.62 (2H, s), 4.05 (2H, q, J = 9.3 Hz), MS (ESI) m/z: 356 (M + H)⁺. Intermediate-49a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.93 (1H, s), 8.25 (1H, s), 7.99 (1H, d, J = 5.9 Hz), 7.55 (1H, d, J = 5.9 Hz), 7.29 (1H, s), 6.40 (1H, tt, J = 54.3 and 3.7 Hz), 5.72 (2H, s), 4.49-4.38 (2H, m), 2.18 (3H, s), MS (ESI) m/z: 339 (M + H)⁺. Intermediate-50a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.93 (1H, s), 7.99 (1H, d, J = 6.2 Hz), 7.60-7.52 (3H, m), 7.14 (1H, d, J = 9.5 Hz), 6.66 (1H, s), 6.02 (2H, s), 3.81 (3H, s), MS (ESI) m/z: 381 (M + H)⁺. Intermediate-51a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.96 (1H, s), 7.99 (1H, d, J = 6.2 Hz), 7.65-7.54 (2H, m), 7.39 (1H, dd, J = 8.6, 2.2 Hz), 7.23 (1H, d, J = 8.6 Hz), 6.40 (1H, tt, J = 54.3, 3.7 Hz), 5.65 (2H, s), 4.40 (2H, td, J = 14.7, 3.7 Hz), MS (ESI) m/z: 358 (M + H)⁺. Intermediate-53a ¹H-NMR (300 MHz, DMSO-d₆) δ 9.00 (1H, s), 8.00 (1H, d, J = 6.6 Hz), 7.58-7.31 (5H, m), 5.77 (2H, s), MS (ESI) m/z: 328 (M + H)⁺. Intermediate-54a ¹H-NMR (300 MHz, CDCl₃) δ 8.27 (1H, s), 8.19 (1H, s), 8.05 (1H, d, J = 5.9 Hz), 7.56 (1H, dd, J = 8.8, 2.2 Hz), 7.45 (1H, d, J = 5.9 Hz), 4.99-4.89 (4H, m), MS (ESI) m/z: 361 (M + H)⁺. Intermediate-55a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.96 (1H, s), 8.35 (1H, d, J = 2.9 Hz), 7.99 (1H, d, J = 6.2 Hz), 7.60-7.54 (2H, m), 7.44 (1H, d, J = 8.8 Hz), 5.79 (2H, s), 4.96 (2H, t, J = 13.2 Hz), MS (ESI) m/z: 393 (M + H)⁺. Intermediate-56a ¹H-NMR (300 MHz, DMSO-d₆) δ 9.00 (1H, s), 7.98 (1H, d, J = 6.2 Hz), 7.56 (1H, d, J = 6.2 Hz), 7.47 (2H, d, J = 8.6 Hz), 7.28 (2H, d, J = 8.6 Hz), 6.78 (1H, tt, J = 51.8, 3.3 Hz), 5.73 (2H, s), MS (ESI) m/z: 360 (M + H)⁺. Intermediate-57a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.96 (1H, s), 8.34 (1H, d, J = 2.9 Hz), 7.99 (1H, d, J = 6.6 Hz), 7.57-7.53 (2H, m), 7.42 (1H, d, J = 8.1 Hz), 6.68 (1H, tt, J = 52.1 and 5.9 Hz), 5.78 (2H, s), 4.70 (2H, t, J = 13.2 Hz), MS (ESI) m/z: 375 (M + H)⁺. Intermediate-58a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.96 (1H, s), 8.30 (1H, d, J = 1.8 Hz), 8.11 (1H, d, J = 1.8 Hz), 7.98 (1H, d, J = 6.2 Hz), 7.56 (1H, d, J = 6.2 Hz), 6.61 (1H, tt, J = 52.0, 5.2 Hz), 5.70 (2H, s), 4.94 (2H, t, J = 14.0 Hz), MS (ESI) m/z: 409 (M + H)⁺. Intermediate-59a ¹H-NMR (300 MHz, DMSO-d₆) δ 9.02 (1H, s), 7.97 (1H, d, J = 5.9 Hz), 7.82 (1H, s), 7.71-7.55 (4H, m), 5.81 (2H, s), MS (ESI) m/z: 312 (M + H)⁺. Table 4-5 Intermediate-60a ¹H-NMR (270 MHz, CDCl₃) δ 8.32 (1H, s), 8.13 (1H, s), 8.02 (1H, d, J = 5.9 Hz), 7.45 (1H, d, J = 5.9 Hz), 7.14 (1H, s), 5.86 (1H, q, J = 6.6 Hz), 4.44 (2H, q, J = 7.9 Hz), 2.07 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 371 (M + H)⁺. Intermediate-61a ¹H-NMR (300 MHz, CDCl₃) δ 8.44 (1H, d, J = 1.5 Hz, 8.13 (1H, s), 8.06 (1H, d, J = 6.6 Hz), 7.47 (1H, d, J = 6.6 Hz), 7.43 (1H, s), 5.58 (2H, s), 3.04-3.00 (2H, m), 2.69-2.60 (2H, m), 2.32 (3H, s), MS (ESI) m/z: 355 (M + H)⁺. Intermediate-62a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.92 (1H, s), 8.22 (1H, s), 7.99 (1H, d, J = 5.9 Hz), 7.55 (1H, d, J = 5.9 Hz), 7.27 (1 H, s), 5.71 (2H, s), 4.32 (2H, t, J = 5.9 Hz), 2.87-2.75 (2H, m), 2.15 (3H, s), MS (ESI) m/z: 371 (M + H)⁺. Intermediate-63a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.95 (1H, s), 8.28 (1H, s), 8.08 (1H, s), 7.97 (1H, d, J = 6.6 Hz), 7.55 (1H, d, J = 5.9 Hz), 5.69 (2H, s), 4.62 (2H, t, J = 12.5 Hz), 1.71 (3H, t, J = 19.8 Hz), MS (ESI) m/z: 373 (M + H)⁺. Intermediate-64a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.97 (1H, s), 8.29 (1H, d, J = 2.2 Hz), 8.07 (1H, d, J = 2.2 Hz), 7.99 (1H, d, J = 6.2 Hz), 7.57 (1H, d, J = 6.2 Hz), 5.69 (2H, s), 4.56 (2H, t, J = 5.9 Hz), 2.90-2.73 (2H, m), MS (ESI) m/z: 391 (M + H)⁺. Intermediate-65a ¹H-NMR (300 MHz, DMSO-d₆) δ 9.05 (1H, s), 8.01 (1H, d, J = 6.2 Hz), 7.98 (1H, s), 7.84 (1H, d, J = 8.4 Hz), 7.62 (1H, d, J = 8.8 Hz), 7.57 (1 H, d, J = 6.2 Hz), 6.19 (2H, s), 3.97 (3H, s), MS (ESI) m/z: 366 (M + H)⁺. Intermediate-66a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.94 (1H, s), 8.28 (1H, s), 7.99 (1H, d, J = 6.2 Hz), 7.55 (1H, d, J = 6.2 Hz), 7.30 (1H, s), 6.69 (1H, tt, J = 51.6, 5.5 Hz), 5.72 (2H, s), 4.72 (2H, t, J = 13.2 Hz), 2.20 (3H, s), MS (ESI) m/z: 389 (M + H)⁺. Intermediate-67a ¹H-NMR (300 MHz, CDCl₃) δ 8.96 (1H, s), 8.25 (1H, d, J = 2.0 Hz), 8.03 (1H, d, J = 2.0 Hz), 7.99 (1H, d, J = 6.2 Hz), 7.57 (1H, d, J = 6.2 Hz), 5.67 (2H, s), 4.18 (2H, d, J = 7.0 Hz), 1.28-1.20 (1H, m), 0.61-0.50 (2H, m), 0.37-0.30 (2H, m), MS (ESI) m/z: 349 (M + H)⁺. Intermediate-68a ¹H-NMR (300 MHz, CDCl₃) δ 8.37 (1H, s), 8.15 (1H, s), 8.03 (1H, d, J = 6.6 Hz), 7.45 (1H, d, J = 5.6 Hz), 7.23 (1H, s), 5.97 (1H, q, J = 7.3 Hz), 4.45 (2H, q, J = 7.3 Hz), 2.29 (3H, s), 2.09 (3H, d, J = 8.8 Hz), MS (ESI) m/z: 371 (M + H)⁺. Intermediate-69a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.97 (1H, s), 7.99 (1H, d, J = 6.2 Hz), 7.62 (1H, d, J = 2.0 Hz), 7.57 (1H, d, J = 6.2 Hz), 7.41 (1H, dd, J = 8.6, 2.0 Hz), 7.27 (1H, d, J = 8.6 Hz), 5.66 (2H, s), 4.86 (2H, q, J = 8.8 Hz), MS (ESI) m/z: 376 (M + H)⁺. Intermediate-70a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.96 (1H, s), 8.15 (1H, d, J = 1.6 Hz), 7.99 (1H, d, J = 6.2 Hz), 7.64 (1H, d, J = 1.6 Hz), 7.56 (1H, d, J = 6.2 Hz), 7.53-7.44 (2H, m), 7.25-7.15 (2H, m), 5.63 (2H, s), 5.35 (2H, s), 2.14 (3H, s), MS (ESI) m/z: 383 (M + H)⁺. Intermediate-71a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.95 (1H, s), 8.09 (1H, d, J = 1.8 Hz), 7.98 (1H, d, J = 6.2 Hz), 7.60 (1H, d, J = 1.8 Hz), 7.56 (1H, d, J = 6.2 Hz), 5.60 (2H, s), 5.13 (1H, quintet, J = 7.4 Hz), 2.44-2.30 (2H, m), 2.18-1.93 (2H, m), 2.10 (3H, s), 1.82-1.56 (2H, m), MS (ESI) m/z: 329 (M + H)⁺. Intermediate-72a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.89 (1H, s), 8.12 (1H, s), 7.97 (1H, d, J = 6.0 Hz), 7.53(1H, d, J = 6.0 Hz), 7.24 (1H, s), 5.67 (2H, s), 3.91 (2H, d, J = 7.0 Hz), 2.16 (3H, s), 1.24-1.10 (1H, m), 0.59-0.50 (2H, m), 0.34-0.25 (2H, m), MS (ESI) m/z: 329 (M + H)⁺. Table 4-6 Intermediate-73a ¹H-NMR (300 MHz, CDCl₃) δ 8.20 (1H, s), 8.18 (1H, d, J = 5.9 Hz), 7.42 (1H, d, J = 5.9 Hz), 7.24 (1H, s), 5.98 (1H, tt, J = 52.7, 3.7 Hz), 5.79 (2H, s), 4.93 (2H, t, J = 12.5 Hz), 2.22 (3H, s), MS (ESI) m/z: 390 (M + H)⁺. Intermediate-74a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.94 (1H, s), 8.23 (1H, s), 7.99 (1H, d, J = 5.9 Hz), 7.55 (1H, d, J = 5.9 Hz), 7.29 (1H, s), 5.72 (2H, s), 4.40 (2H, t, J = 12.5 Hz), 2.19 (3H, s), 1.74 (3H, t, J = 19.4 Hz), MS (ESI) m/z: 353 (M + H)⁺. Intermediate-75a ¹H-NMR (300 MHz, DMSO-d₆) δ 8.92 (1H, s), 7.98 (1H, d, J = 6.2 Hz), 7.56 (1H, d, J = 6.2 Hz), 7.31-7.23 (2H, m), 6.98 (1H, d, J = 8.8 Hz), 5.59 (2H, s), 4.25 (2H, t, J = 12.1 Hz), 2.15 (3H, s), 1.74 (3H, t, J = 19.4 Hz), MS (ESI) m/z: 352 (M + H)⁺. Intermediate-76a ¹H-NMR (300 MHz, CDCl₃) δ 8.05-8.01 (2H, m), 7.47 (1H, d, J = 6.2 Hz), 7.21-7.14 (2H, m), 6.79 (1H, d, J = 9.2 Hz), 6.11 (1 H, tt, J = 55.2 and 4.0 Hz), 5.76 (1H, q, J = 7.0 Hz), 4.19 (2H, td, J = 13.0 and 4.0 Hz), 2.24 (3H, s), 2.03 (3H, d, J = 7.0 Hz), MS (ESI) m/z: 352 (M + H)⁺. Intermediate-77a ¹H-NMR (300 MHz, CDCl₃) δ 8.07-8.03 (2H, m), 7.48 (1H, d, J = 5.9 Hz), 7.01 (2H, s), 6.08 (1H, tt, J = 55.0 and 4.4 Hz), 5.49 (2H, s), 4.00 (2H, td, J = 13.9 and 4.4 Hz), 2.28 (6H, s), MS (ESI) m/z: 352 (M + H)⁺. Intermediate 78a ¹H-NMR (300 MHz, CDCl₃) δ 8.08-8.01 (2H, m), 7.48 (1H, d, J = 6.2 Hz), 7.20 (1H, d, J = 7.3 Hz), 6.93 (1H, d, J = 7.7 Hz), 6.79 (1H, s), 6.10 (1H, tt, J = 55.0 and 4.0 Hz), 5.55 (2H, s), 4.16 (2H, td, J = 12.8 and 4.0 Hz), 2.24 (3H, s), MS (ESI) m/z: 338 (M + H)⁺. Intermediate-79a ¹H-NMR (270 MHz, CDCl₃) δ 8.06-8.00 (2H, m), 7.47 (1H, d, J = 6.3 Hz), 7.21-7.13 (2H, m), 6.78 (1H, d, J = 9.2 Hz), 5.76 (1H, q, J = 6.8 Hz), 4.10 (2H, t, J = 11.2 Hz), 2.25 (3H, s), 2.03 (3H, d, J = 6.8 Hz), 1.78 (3H, t, J = 18.8 Hz), MS (ESI) m/z: 366 (M + H)⁺. Intermediate-80a ¹H-NMR (270 MHz, CDCl₃) δ 8.07-8.00 (2H, m), 7.47 (1H, d, J = 6.2 Hz), 7.22-7.13 (2H, m), 6.79 (1H, d, J = 9.2 Hz), 6.10 (1H, tt, J = 55.3 and 3.9 Hz), 5.76 (1H, q, J = 6.9 Hz), 4.19 (2H, td, J = 12.9 and 3.9 Hz), 2.24 (3H, s), 2.03 (3H, d, J = 6.9 Hz), MS (ESI) m/z: 352 (M + H)⁺. Intermediate-81a ¹H-NMR (270 MHz, CDCl₃) δ 8.09-8.03 (2H, m), 7.48 (1H, d, J = 5.9 Hz), 7.27-7.09 (3H, m), 6.50 (1H, t, J = 73.5 Hz), 5.55 (2H, s), 2.29 (3H, s), MS (ESI) m/z: 324 (M + H)⁺.

Representative Procedure for Method E

The following preparation of Intermediate-1b represents the Method E.

Intermediate-1b ethyl 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate

To a solution of 4-chloro-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine (6.31 g, 17.7 mmol, Intermediate-1a) in DMF/EtOH (2:1, 180 mL), palladium(II) acetate (1.19 g, 5.31 mmol), 1,3-bis(diphenylphosphino)propane (2.19 g, 5.31 mmol) and triethylamine (7.4 mL, 53.1 mmol) are added. The mixture is heated at 80° C. for 3 hours under CO gas atmosphere. The reaction mixture is diluted with EtOAc (400 mL) and washed with water (200 mL). The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography eluting with hexane/EtOAc (4:1-1:4) to give 5.13 g (74% yield) of title compound as a pale yellow solid.

¹H-NMR (300 MHz, CDCl₃) delta 8.64 (1H, s), 8.48 (1H, d, J=5.9 Hz), 8.07 (1H, s), 7.75 (1H, d, J=6.6 Hz), 7.48 (1H, s), 5.58 (2H, s), 4.77 (2H, q, J=8.6 Hz), 4.54 (2H, q, J=7.3 Hz), 2.21 (3H, s), 1.49 (3H, t, J=7.3 Hz), MS (ESI) m/z: 395 (M+H)⁺.

Intermediate-1c 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylic acid

The title compound is prepared in 96% yield (183 mg, a pale yellow solid) from ethyl 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate (205 mg, 0.52 mmol, Intermediate-1b) in a similar manner to Step-2 of Intermediate-A6.

MS (ESI) m/z: 365 (M−H)⁻.

Intermediate-1h N-(2-aminoethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide hydrochloride <Step 122 tert-butyl (2-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamido)ethyl)carbamate

The title compound is prepared in >99% yield (278 mg, a colorless syrup) from 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylic acid (200 mg, 0.55 mmol, Intermediate-1c) and tert-butyl (2-aminoethyl)carbamate (131 mg, 0.82 mmol) in a similar manner to Step-1 of Intermediate-A7.

¹H-NMR (300 MHz, CDCl₃) delta 8.81 (1H, s), 8.35 (1H, br s), 8.25 (1H, d, J=5.1 Hz), 8.07 (1H, s), 8.02 (1H, s), 7.69 (1H, d, J=5.1 Hz), 7.46 (1H, s), 5.56 (2H, s), 4.76 (2H, q, J=8.8 Hz), 3.70-3.58 (2H, m), 3.50-3.38 (2H, m), 2.20 (3H, s), 1.42 (9H, s),

MS (ESI) m/z: 509 (M+H)⁺.

<Step 2> N-(2-aminoethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide hydrochloride

A mixture of tert-butyl (2-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamido)ethyl)carbamate (278 mg, 0.55 mmol, Step-1) and 4 M hydrogen chloride in dioxane solution (10 mL) is stirred at rt for 1 hour. After removal of the solvent, the residual solid is washed with diisopropylether-hexane to give 243 mg (>99%) of the title compound as a white solid.

MS (ESI) m/z: 409 (M+H)⁺.

Representative Procedure for Method F

The following preparation of Intermediate-36b represents the Method F.

Intermediate-36b: phenyl 2-(2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate

A mixture of 4-chloro-2-(2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-2H-pyrazolo[4,3-c]pyridine (310 mg, 0.82 mmol), phenyl formate (201 mg, 1.64 mmol), palladium(II) acetate (5 mg, 0.03 mmol), Xantphos (57 mg, 0.10 mmol), and triethylamine (0.23 mL, 1.64 mmol) in MeCN is refluxed with stirring for 12 hours. After cooling to rt, the solvent is removed in vacuo. The residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (1:1-1:3) to give 152 mg (40% yield) of the title compound as a yellow solid.

¹H-NMR (270 MHz, DMSO-d₆) delta 8.85 (1H, s), 8.57 (1H, d, J=5.9 Hz), 8.28 (1H, s), 7.84-7.82 (2H, m), 7.51-7.45 (2H, m), 7.35-7.29 (3H, m), 4.96 (4H, s), MS (ESI) m/z: 463 (M+H)⁺.

The following intermediate compounds are prepared using the Method E or F from starting materials shown in Table 5-1 to 5-4. Spectral data of the intermediate compounds are shown in Table 6-1 to 6-6.

ID Name Method Starting Material Table 5-1 Intermediate-1e ethyl 6-methyl-2-((5-methyl-6-(2,2,2- E Intermediate-1d trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo- [4,3-c]pyridine-4-carboxylate Intermediate-2b ethyl 2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3- E Intermediate-2a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-4b ethyl 2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl- E Intermediate-4a 2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-5b ethyl 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3- E Intermediate-5a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-6b ethyl 2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3- E Intermediate-6a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-10b ethyl 2-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)- E Intermediate-10a 2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-11b ethyl 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3- E Intermediate-11a yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate (single enantiomer) Intermediate-11c phenyl 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin- F Intermediate-11a 3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate (single enantiomer) Intermediate-12b ethyl 2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3- E Intermediate-12a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-13b ethyl 2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3- E Intermediate-13a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-14b ethyl 2-(4-(2,2,2-trifluoroethoxy)benzyl)-2H- E Intermediate-14a pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-15b ethyl 2-((6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3- E Intermediate-15a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-19b ethyl 2-(6-(4-fluorophenoxy)-5-methylpyridin-3- E Intermediate-19a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-20b ethyl 2-((4-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3- E Intermediate-20a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-21b ethyl 2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3- E Intermediate-21a yl)methyl)-2H-prazolo[4,3-c]pyridine-4-carboxylate Intermediate-22b ethyl 2-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3- E Intermediate-22a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-23b ethyl 2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2- E Intermediate-23a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-24b ethyl 2-((5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3- E Intermediate-24a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-25b ethyl 2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2H- E Intermediate-25a pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-26b ethyl 2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-2H- E Intermediate-26a pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-27b ethyl 2-((5-methyl-6-(2,2,3,3- E Intermediate-27a tetrafluoropropoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-28b ethyl 2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4- E Intermediate-28a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-30b ethyl 2-((1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol- E Intermediate-30a 3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Table 5-2 Intermediate-31b ethyl 2-((5-methyl-6-(2-(2,2,2- E Intermediate-31a trifluoroethoxy)ethoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-32b ethyl 2-(2-methoxy-642,2,2-trifluoroethoxy)pyridin-3- E Intermediate-32a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-33b ethyl 2-(2-(4-(trifluoromethyl)phenoxy)ethyl)-2H- E Intermediate-33a pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-34b ethyl 2-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2- E Intermediate-34a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-35b ethyl 2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3- E Intermediate-35a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-37b phenyl 2-((5-cyclopropyl-6-(2,2,2- F Intermediate-37a trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo- [4,3-c]pyridine-4-carboxylate Intermediate-38b ethyl 2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin- E Intermediate-38a 3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-39b phenyl 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin- F Intermediate-39a 3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate (single enantiomer) Intermediate-40b ethyl 2-((5-methyl-2-phenyl-2H-1,2,3-triazol-4- E Intermediate-40a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-41b ethyl 2-((6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)- E Intermediate-41a 2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-42b ethyl 2-((6-(cyclopropylmethoxy)-5-methylpyridin-3- E Intermediate-42a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-43b ethyl 2-((5-methyl-6-((2,2,2- E Intermediate-43a trifluoroethyl)annino)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-44b ethyl 2-(3-methyl-4-(trifluoromethoxy)benzyl)-2H- E Intermediate-44a pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-45b ethyl 2-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)- E Intermediate-45a 2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-47b ethyl 2-((1-(2,2,2-trifluoroethoxy)isoquinolin-4- F Intermediate-47a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-48b ethyl 2-(4-((2,2,2-trifluoroethoxy)methyl)benzyl)-2H- E Intermediate-48a pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-49b ethyl 2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2- E Intermediate-49a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-50b ethyl 2-((1-methyl-5-(trifluoromethoxy)-1H-indol-2- E Intermediate-50a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-51b ethyl 2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-2H- E Intermediate-51a pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-52b ethyl 2-((5-methyl-6-((2,2,2- E Intermediate-52a trifluoroethoxy)methyl)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-53b phenyl 2-(3-(trifluoromethoxy)benzyl)-2H-pyrazolo- F Intermediate-53a [4,3-c]pyridine-4-carboxylate Intermediate-54b phenyl 2-(2-((3-fluoro-5-(trifluoronnethyl)pyridin-2- F Intermediate-54a yl)oxy)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-55b ethyl 2-((5-(2,2,3,3,3-pentafluoropropoxy)pyridin-2- E Intermediate-55a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Table 5-3 Intermediate-56b ethyl 2-(4-(1,1,2,2-tetrafluoroethoxy)benzyl)-2H- E Intermediate-56a pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-57b ethyl 2-((5-(2,2,3,3-tetrafluoropropoxy)pyridin-2- E Intermediate-57a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-58b ethyl 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin- E Intermediate-58a 3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-59b phenyl 2-(3-(trifluoromethyl)benzyl)-2H-pyrazolo- F Intermediate-59a [4,3-c]pyridine-4-carboxylate Intermediate-60b ethyl 2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2- E Intermediate-60a yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate (single enantiomer) Intermediate-61b phenyl 2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3- F Intermediate-61a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-62b ethyl 2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2- E Intermediate-62a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-63b phenyl 2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3- F Intermediate-63a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-64b ethyl 2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3- E Intermediate-64a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-65b ethyl 2-((1-methyl-5-(trifluoromethyl)-1H- E Intermediate-65a benzo[d]imazol-2-yl)methyl)-2H-pyrazolo- [4,3-c]pyridine-4-carboxylate Intermediate-66b ethyl 2-((4-methyl-5-(2,2,3,3- E Intermediate-66a tetrafluoropropoxy)pyridin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-67b ethyl 2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3- E Intermediate-67a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-68b ethyl 2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2- E Intermediate-68a yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate (single enantiomer, antipode of Intermediate-60b) Intermediate-69b ethyl 2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-2H- E Intermediate-69a pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-70b ethyl 2-((6-((4-fluorobenzyl)oxy)-5-methylpyridin-3- E Intermediate-70a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-71b ethyl 2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)- E Intermediate-71a 2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-72b ethyl 2-((5-(cyclopropylmethoxy)-4-methylpyridin-2- E Intermediate-72a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-73b ethyl 2-((5-methyl-6-(2,2,3,3- E Intermediate-73a tetrafluoropropoxy)pyridazin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-74b ethyl 2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2- E Intermediate-74a yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-75b ethyl 2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-2H- E Intermediate-75a pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-76b ethyl 2-(1-(4-(2,2-difluoroethoxy)-3- E Intermediate-76a methylphenyl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxylate (single enantiomer) Intermediate-77b ethyl 2-(4-(2,2-difluoroethoxy)-3,5-dimethylbenzyl)-2H- E Intermediate-77a pyrazolo[4,3-c]pyridine-4-carboxylate Table 5-4 Intermediate-78b ethyl 2-(3-(2,2-difluoroethoxy)-4-methylbenzyl)-2H- E Intermediate-78a pyrazolo[4,3-c]pyridine-4-carboxylate Intermediate-79b ethyl 2-(1-(4-(2,2-difluoropropoxy)-3- E Intermediate-79a methylphenyl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxylate (single enantiomer) Intermediate-80b ethyl 2-(1-(4-(2,2-difluoroethoxy)-3- E Intermediate-80a methylphenyl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxylate (single enantiomer, antipode of Intermediate-76b) Intermediate-81b ethyl 2-(4-(difluoromethoxy)-3-methylbenzyl)-2H- E Intermediate-81a pyrazolo[4,3-c]pyridine-4-carboxylate

ID# data Table 6-1 Intermediate-1e ¹H-NMR (300 MHz, CDCl₃) δ 8.54 (1H, s), 8.05 (1H, s), 7.55 (1H, s), 7.46 (1H, s), 5.54 (2H, s), 4.76 (2H, q, J = 8.6 Hz), 4.54 (2H, q, J = 7.1 Hz), 2.73 (3H, s), 2.21 (3H, s), 1.48 (3H, t, 7.0 Hz), MS (ESI) m/z: 409 (M + H)⁺. Intermediate-2b ¹H-NMR (300 MHz, CDCl₃) δ 8.64 (1H, s), 8.48 (1H, d, J = 6.2 Hz), 8.06 (1H, d, J = 2.2 Hz), 7.75 (1H, dd, J = 6.2, 1.1 Hz), 7.45 (1H, d, J =1.1 Hz), 6.14 (1H, tt, J = 55.4, 4.0 Hz), 5.57 (2H, s), 4.60-4.50 (4H, m), 2.19 (3H, s), 1.49 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 377 (M + H)⁺. Intermediate-4b ¹H-NMR (300 MHz, CDCl₃) δ 8.66 (1H, s), 8.48 (1H, d, J = 6.2 Hz), 8.24 (1H, d, J = 2.2 Hz), 7.75 (1H, d, J = 6.2 Hz), 7.68 (1H, dd, J = 8.4, 2.2 Hz), 6.89 (1H, d, J = 8.4 Hz), 5.61 (2H, s), 4.76 (2H, q, J = 8.4 Hz), 4.54 (2H, q, J = 7.0 Hz), 1.49 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 381 (M + H)⁺. Intermediate-5b ¹H-NMR (300 MHz, DMSO-d₆) δ 9.10 (1H, s), 8.35 (1H, d, J = 6.6 Hz), 8.32 (1H, d, J = 2.2 Hz), 8.13 (1H, d, J = 2.2 Hz), 7.81 (1H, d, J = 6.6 Hz), 5.78 (2H, s), 5.07 (2H, q, J = 8.8 Hz), 4.42 (2H, q, J = 7.3 Hz), 1.38 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 415 (M + H)⁺. Intermediate-6b ¹H-NMR (300 MHz, DMSO-d₆) δ 9.10 (1H, s), 8.34 (1H, d, J = 6.2 Hz), 8.30 (1H, d, J = 1.8 Hz), 8.09 (1H, d, J = 1.8 Hz), 7.80 (1H, d, J = 6.2 Hz), 6.39 (1H, tt, J = 54.7, 3.3 Hz), 5.77 (2H, s), 4.64 (2H, td, J = 15.0, 3.3 Hz), 4.42 (2H, q, J = 7.0 Hz), 1.38 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 397 (M + H)⁺. Intermediate-10b ¹H-NMR (300 MHz, CDCl₃) δ 8.64 (1H, s), 8.48 (1H, d, J = 6.2 Hz), 8.24 (1H, d, J = 2.6 Hz), 7.75 (1H, d, J = 6.2 Hz), 7.62 (1H, dd, J = 8.4, 2.6 Hz), 6.77 (1H, d, J = 8.4 Hz), 5.60 (2H, s), 4.58-4.50 (4H, m), 2.68-2.54 (2H, m), 1.49 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 395 (M + H)⁺. Intermediate-11b ¹H-NMR (300 MHz, CDCl₃) δ 8.68 (1H, s), 8.47 (1H, d, J = 6.6 Hz), 8.03 (1H, d, J = 2.2 Hz), 7.76 (1H, d, J = 6.6 Hz), 7.46 (1H, d, J = 2.2 Hz), 5.83 (1H, q, J = 6.6 Hz), 4.76 (2H, q, J = 8.8 Hz), 4.54 (2H, q, J = 7.3 Hz), 2.21 (3H, s), 2.07 (3H, d, J = 6.6 Hz), 1.50 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 409 (M + H)⁺. Intermediate-11c 1H-NMR (300 MHz, CDCl₃) δ 8.66 (1H, s), 8.56 (1H, d, J = 5.9 Hz), 8.02 (1H, s), 7.84 (1H, d, J = 6.6 Hz), 7.50-7.42 (3H, m), 7.35-7.25 (3H, m), 5.84 (1H, q, J = 6.6 Hz), 4.75 (2H, q, J = 8.8 Hz), 2.21 (3H, s), 2.08 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 457 (M + H)+. Intermediate-12b ¹H-NMR (300 MHz, CDCl₃) δ 8.70 (1H, s), 8.49 (1H, d, J = 6.2 Hz), 8.02 (1H, s), 7.75 (1H, d, J = 6.2 Hz), 7.46 (1H, dd, J = 9.9, 2.2 Hz), 5.62 (2H, s), 4.83 (2H, q, J = 8.4 Hz), 4.55 (2H, q, J = 7.3 Hz), 1.50 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 399 (M + H)⁺. Intermediate-13b ¹H-NMR (300 MHz, DMSO-d₆) δ 9.08 (1H, s), 8.35 (1H, s), 8.34 (1H, d, J = 6.2 Hz), 7.86 (1H, dd, J = 8.4, 2.2 Hz), 7.80 (1H, d, J = 5.9 Hz), 6.95 (1H, d, J = 8.4 Hz), 6.64 (1H, tt, J = 51.7, 5.1 Hz), 5.77 (2H, s), 4.84 (2H, t, J = 13.9 Hz), 4.42 (2H, q, J = 7.0 Hz), 1.39 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 413 (M + H)⁺. Intermediate-14b ¹H-NMR (300 MHz, DMSO-d₆) δ 9.03 (1H, s), 8.35 (1H, d, J = 5.9 Hz), 7.81 (1H, d, J = 5.9 Hz), 7.43 (2H, d, J = 8.8 Hz), 7.06 (2H, d, J = 8.8 Hz), 5.73 (2H, s), 4.75 (2H, q, J = 8.8 Hz), 4.43 (2H, q, J = 7.3 Hz), 1.39 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 380 (M + H)⁺. Intermediate-15b ¹H-NMR (300 MHz, CDCl₃) δ 8.66 (1H, s), 8.48 (1H, d, J = 6.2 Hz), 8.24 (1H, d, J = 2.2 Hz), 7.75 (1H, d, J = 6.2 Hz), 7.68 (1H, dd, J = 8.8, 2.2 Hz), 6.88 (1H, d, J = 8.8 Hz), 5.62 (2H, s), 4.92-4.74 (2H, m), 4.55 (2H, q, J = 7.0 Hz), 1.49 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 431 (M + H)⁺. Table 6-2 Intermediate-19b ¹H-NMR (300 MHz, CDCl₃) δ 8.64 (1H, s), 8.48 (1H, d, J = 6.2 Hz), 8.03 (1H, d, J = 1.8 Hz), 7.76 (1H, d, J = 6.2 Hz), 7.54 (1H, d, J = 1.8 Hz), 7.08 (4H, d, J = 6.6 Hz), 5.58 (2H, s), 4.54 (2H, q, J = 7.0 Hz), 2.33 (3H, s), 1.50 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 407 (M + H)⁺. Intermediate-20b ¹H-NMR (300 MHz, CDCl₃) δ 8.50-8.46 (2H, m), 8.11 (1H, s), 7.75 (1H, dd, J = 6.2, 0.7 Hz), 6.77 (1H, s), 5.64 (2H, s), 4.77 (2H, q, J = 8.4 Hz), 4.52 (2H, q, J = 7.3 Hz), 2.26 (3H, s), 1.48 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 395 (M + H)⁺. Intermediate-21b ¹H-NMR (300 MHz, CDCl₃) δ 8.63 (1H, s), 8.48 (1H, d, J = 5.9 Hz), 8.07 (1H, d, J = 2.2 Hz), 7.75 (1H, d, J = 5.9 Hz), 7.43 (1H, d, J = 2.2 Hz), 5.56 (2H, s), 4.59-4.50 (4H, m), 2.71-2.54 (2H, m), 2.16 (3H, s), 1.49 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 409 (M + H)⁺. Intermediate-22b ¹H-NMR (300 MHz, CDCl₃) δ 8.81 (1H, s), 8.49 (1H, d, J = 6.2 Hz), 7.75 (1H, d, J= 6.2 Hz), 7.34 (1H, s), 5.89 (2H, s), 4.94 (2H, q, J = 8.4 Hz), 4.55 (2H, q, J = 7.0 Hz), 2.26 (3H, s), 1.50 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 396 (M + H)⁺. Intermediate-23b ¹H-NMR (300 MHz, CDCl₃) δ 8.78 (1H, s), 8.47 (1H, d, J = 6.6 Hz), 8.13 (1H, s), 7.75 (1H, d, J = 6.6 Hz), 7.15 (1H, s), 5.70 (2H, s), 4.55 (2H, q, J = 7.3 Hz), 4.44 (2H, q, J = 8.1 Hz), 2.26 (3H, s), 1.50 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 395 (M + H)⁺. Intermediate-24b ¹H-NMR (300 MHz, CDCl₃) δ 8.66 (1H, s), 8.49 (1H, d, J = 5.9 Hz), 7.80-7.74 (2H, m), 7.12 (1H, d, J = 1.8 Hz), 5.60 (2H, s), 4.83 (2H, q, J = 8.4 Hz), 4.54 (2H, q, J = 7.3 Hz), 3.84 (3H, s), 1.49 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 411 (M + H)⁺. Intermediate-25b ¹H-NMR (300 MHz, CDCl₃) δ 8.60 (1H, s), 8.46 (1H, d, J = 5.9 Hz), 7.75 (1H, d, J = 6.2 Hz), 7.24-7.19 (2H, m), 6.81-6.77 (1H, m), 5.57 (2H, s), 4.53 (2H, q, J = 7.0 Hz), 4.35 (2H, q, J = 8.1 Hz), 2.25 (3H, s), 1.49 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 394 (M + H)⁺. Intermediate-26b ¹H-NMR (300 MHz, DMSO-d₆) δ 8.99 (1H, s), 8.33 (1H, d, J = 5.9 Hz), 7.80 (1H, d, J = 5.9 Hz), 7.27 (1H, s), 7.25 (1H, d, J = 5.9 Hz), 6.99 (1H, d, J = 8.8 Hz), 6.36 (1H, tt, J = 54.7, 3.3 Hz), 5.66 (2H, s), 4.41 (2H, q, J = 7.3 Hz), 4.28 (2H, td, J = 14.7, 3.3 Hz), 2.13 (3H, s), 1.38 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 376 (M + H)⁺. Intermediate-27b ¹H-NMR (300 MHz, DMSO-d₆) δ 9.08 (1H, s), 8.35 (1H, d, J = 5.9 Hz), 8.19 (1H, d, J = 2.2 Hz), 7.82 (1H, d, J = 6.6 Hz), 7.71 (1H, s), 6.66 (1H, tt, J = 52.1, 5.1 Hz), 5.74 (2H, s), 4.85 (2H, t, J = 13.9 Hz), 4.43 (2H, q, J = 7.3 Hz), 2.15 (3H, s), 1.40 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 427 (M + H)⁺. Intermediate-28b ¹H-NMR (300 MHz, CDCl₃) δ 8.71 (1H, s), 8.50 (1H, d, J = 6.2 Hz), 7.77 (1H, d, J = 6.2 Hz), 6.67 (1H, s), 6.50 (1H, s), 5.59 (2H, s), 4.74 (2H, q, J = 8.8 Hz), 4.56 (2H, q, J = 7.0 Hz), 2.41 (3H, s), 1.50 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 395 (M + H)⁺. Intermediate-30b ¹H-NMR (300 MHz, DMSO-d₆) δ 9.11 (1H, s), 8.89 (1H, s), 8.66 (1H, d, J = 2.2 Hz), 8.40-8.30 (2H, m), 8.05 (1H, d, J = 8.8 Hz), 7.84 (1H, d, J = 5.9 Hz), 6.65 (1H, d, J = 2.2 Hz), 5.94 (2H, s), 4.44 (2H, q, J = 6.6 Hz), 1.40 (3H, t, J = 6.6 Hz), MS (ESI) m/z: 417 (M + H)⁺. Intermediate-31b ¹H-NMR (300 MHz, DMSO-d₆) δ 9.06 (1H, s), 8.35 (1H, d, J =5.9 Hz), 8.15 (1H, s), 7.81 (1H, d, J = 5.9 Hz), 7.49 (1H, s), 5.71 (2H, s), 4.47-4.37 (4H, m), 4.13 (2H, q, J = 9.5 Hz), 3.95-3.90 (2H, m), 2.11 (3H, s), 1.40 (3H, t, J = 6.6 Hz), MS (ESI) m/z: 439 (M + H)⁺. Intermediate-32b ¹H-NMR (300 MHz, DMSO-d₆) δ 8.90 (1H, s), 8.35 (1H, d, J = 5.9 Hz), 7.80 (1H, d, J = 6.6 Hz), 7.70 (1H, d, J = 8.0 Hz), 6.56 (1H, d, J = 8.1 Hz), 5.69 (2H, s), 5.02 (2H, q, J = 8.8 Hz), 4.43 (2H, q, J = 7.3 Hz), 3.91 (3H, s), 1.40 (3H, t, J = 6.6 Hz), MS (ESI) m/z: 411 (M + H)⁺. Table 6-3 Intermediate-33b ¹H-NMR (300 MHz, CDCl₃) δ 8.81 (1H, s), 8.48 (1H, d, J = 6.2 Hz), 7.74 (1H, d, J = 6.2 Hz), 7.52 (2H, d, J = 8.8 Hz), 6.94 (2H, d, J = 8.8 Hz), 4.91 (2H, t, J = 5.1 Hz), 4.60-4.53 (4H, m), 1.52 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 380 (M + H)⁺. Intermediate-34b ¹H-NMR (300 MHz, DMSO-d₆) δ 9.09 (1H, s), 8.36 (1H, d, J = 5.9 Hz), 8.25 (1H, s), 7.80 (1H, d, J = 5.9 Hz), 5.88 (2H, s), 5.05 (2H, q, J = 9.5 Hz), 4.45 (2H, q, J = 7.3 Hz), 2.38 (3H, s), 1.39 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 396 (M + H)⁺. Intermediate-35b ¹H-NMR (300 MHz, DMSO-d₆) δ 9.07 (1H, s), 8.35 (1H, d, J = 5.9 Hz), 8.18 (1H, d, J = 2.2 Hz), 7.82 (1H, d, J = 5.9 Hz), 7.69 (1H, d, J = 2.2 Hz), 5.74 (2H, s), 4.56 (2H, t, J = 12.5 Hz), 4.44 (2H, q, J = 7.3 Hz), 2.15 (3H, s), 1.73 (3H, t, J = 19.1 Hz), 1.40 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 391 (M + H)⁺. Intermediate-37b ¹H-NMR (300 MHz, CDCl₃) δ 8.60-8.56 (2H, m), 8.00 (1H, s), 7.84 (1H, d, J = 6.6 Hz), 7.46 (2H, t, J = 8.0 Hz), 7.34-7.26 (3H, m), 7.22 (1H, s), 5.56 (2H, s), 4.77 (2H, q, J = 8.0 Hz), 2.18-2.01 (1H, m), 1.00-0.95 (2H, m), 0.69-0.65 (2H, m), MS (ESI) m/z: 469 (M + H)⁺. Intermediate-38b ¹H-NMR (300 MHz, CDCl₃) δ 8.73 (1H, s), 8.49 (1H, d, J = 6.2 Hz), 8.36 (1H, s), 8.27 (1H, s), 7.77 (1H, d, J = 6.2 Hz), 7.64 (2H, s), 5.69 (2H, s), 4.55 (2H, q, J = 7.0 Hz), 2.57 (3H, s), 1.50 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 397 (M + H)⁺. Intermediate-39b ¹H-NMR (300 MHz, CDCl₃) δ 8.66 (1H, s), 8.56 (1H, d, J = 5.9 Hz), 8.02 (1H, d, J = 2.2 Hz), 7.84 (1H, d, J = 5.9 Hz), 7.50-7.43 (3H, m), 7.35-7.25 (3H, m), 5.84 (1H, q, J = 6.6 Hz), 4.75 (2H, q, J = 8.8 Hz), 2.21 (3H, s), 2.08 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 457 (M + H)⁺. Intermediate-40b ¹H-NMR (300 MHz, DMSO-d₆) δ 9.13 (1H, s), 8.37 (1H, d, J = 5.9 Hz), 7.93 (2H, d, J = 8.1 Hz), 7.82 (1H, d, J = 5.9 Hz), 7.54 (2H, t, J = 8.1 Hz), 7.39 (1H, t, J = 7.3 Hz), 6.03 (2H, s), 4.45 (2H, q, J = 6.6 Hz), 2.35 (3H, s), 1.41 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 363 (M + H)⁺. Intermediate-41b ¹H-NMR (300 MHz, DMSO-d₆) δ 9.11 (1H, s), 8.37 (1H, d, J = 5.9 Hz), 7.84-7.79 (2H, m), 6.98-6.93 (2H, m), 5.86 (2H, s), 4.89 (2H, q, J = 9.5 Hz), 4.45 (2H, q, J = 7.3 Hz), 1.41 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 381 (M + H)⁺. Intermediate-42b ¹H-NMR (300 MHz, DMSO-d₆) δ 9.05 (1H, s), 8.35 (1H, d, J = 5.9 Hz), 8.13 (1H, d, J = 2.2 Hz), 7.81 (1H, d, J = 5.9 Hz), 7.61 (1H, d, J = 2.2 Hz), 5.69 (2H, s), 4.43 (2H, q, J = 7.3 Hz), 4.10 (2H, d, J =6.6 Hz), 2.11 (3H, s), 1.39 (3H, t, J = 7.3 Hz), 1.28-1.15 (1H m), 0.55-0.48 (2H, m), 0.32-0.28 (2H, m), MS (ESI) m/z: 367 (M + H)⁺. Intermediate-43b ¹H-NMR (300 MHz, CDCl₃) δ 8.60 (1H, s), 8.47 (1H, d, J = 6.2 Hz), 8.12 (1H, s), 7.75 (1H d, J = 6.2 Hz), 7.32 (2H, s), 5.52 (2H, s), 4.53 (2H, q, J = 7.0 Hz), 4.51-4.45 (1H, m), 4.32-4.20 (2H, m), 2.12 (3H, s), 1.49 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 394 (M + H)⁺. Intermediate-44b ¹H-NMR (300 MHz, CDCl₃) δ 8.67 (1H, s), 8.48 (1H, d, J = 6.2 Hz), 7.76 (1H, d, J = 6.2 Hz), 7.26-7.21 (3H, m), 5.62 (2H, s), 4.54 (2H, q, J = 7.0 Hz), 2.30 (3H, s), 1.49 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 380 (M + H)⁺. Intermediate-45b ¹H-NMR (300 MHz, CDCl₃) δ 8.73 (1H, s), 8.51 (1H, d, J = 6.2 Hz), 8.13 (1H, d, J = 5.1 Hz), 7.77 (1H, d, J = 6.2 Hz), 6.84 (1H, d, J = 5.1 Hz), 6.68 (1H, s), 5.65 (2H, s), 4.75 (2H, q, J = 8.4 Hz), 4.55 (2H, q, J = 7.0 Hz), 1.50 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 381 (M + H)⁺. Intermediate-47b ¹H-NMR (300 MHz, CDCl₃) δ 8.55-8.45 (2H, m), 8.36 (1H, d, J = 7.7 Hz), 8.15 (1H, s), 7.88-7.76 (2H, m), 7.73-7.61 (2H, m), 5.99 (2H, s), 5.00 (2H, q, J = 8.4 Hz), 4.46 (2H, q, J = 7.0 Hz), 1.42 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 431 (M + H)⁺. Table 6-4 Intermediate-48b ¹H-NMR (300 MHz, DMSO-d₆) δ 9.08 (1H, s), 8.36 (1H, d, J = 5.9 Hz), 7.83 (1H, d, J = 5.9 Hz), 7.42 (2H, d, J = 8.1 Hz), 7.35 (2H, d, J = 8.1 Hz), 5.80 (2H, s), 4.64 (2H, s), 4.44 (2H, q, J = 7.3 Hz), 4.08 (2H, q, J =9.5 Hz), 1.40 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 394 (M + H)⁺. Intermediate-49b MS (ESI) m/z: 377 (M + H)⁺. Intermediate-50b ¹H-NMR (300 MHz, CDCl₃) δ 8.56 (1H, s), 8.48 (1H, d, J = 6.2 Hz), 7.76 (1H, d, J = 6.2 Hz), 7.51 (1H, s), 7.35-7.26 (1H, m), 7.20-7.11 (1H, m), 6.77 (1H, s), 5.87 (2H, s), 4.49 (2H, q, J = 7.0 Hz), 3.68 (3H, s), 1.45 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 419 (M + H)⁺. Intermediate-51b ¹H-NMR (300 MHz, CDCl₃) δ 8.64 (1H, s), 8.48 (1H, d, J = 6.2 Hz), 7.76 (1H, dd, J = 6.2, 0.9 Hz), 7.42 (1H, d, J = 2.2 Hz), 7.35-7.22 (1H, m), 6.94 (1H, d, J = 8.4 Hz), 6.14 (1H, tt, J = 55.0, 4.0 Hz), 5.58 (2H, s), 4.54 (2H, q, J = 7.3 Hz), 4.24 (2H, td, J = 12.8, 4.0 Hz), 1.49 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 396 (M + H)⁺. Intermediate-52b ¹H-NMR (300 MHz, CDCl₃) δ 8.70 (1H, s), 8.50-8.46 (2H, m), 7.76 (1H, d, J = 5.5 Hz), 7.49 (1H, s), 5.66 (2H, s), 4.81 (2H, s), 4.55 (2H, q, J = 7.0 Hz), 3.88 (2H, q, J = 8.8 Hz), 2.38 (3H, s), 1.50 (3H, t, J = 6.9 Hz), MS (ESI) m/z: 409 (M + H)⁺. Intermediate-53b ¹H-NMR (300 MHz, CDCl₃) δ 8.68 (1H, s), 8.58 (1H, d, J = 5.9 Hz), 7.85 (1H, d, J = 5.9 Hz), 7.49-7.39 (3H, m), 7.34-7.21 (6H, m), 5.69 (2H, s), 4.44 (2H, q, J = 8.1 Hz), 2.26 (3H, s), 1.50 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 414 (M + H)⁺. Intermediate-54b ¹H-NMR (300 MHz, CDCl₃) δ 8.78 (1H, s), 8.57 (1H, d, J = 6.6 Hz), 8.18 (1H, s), 7.83 (1H, d, J = 6.6 Hz), 7.55-7.45 (3H, m), 7.35-7.27 (3H, m), 5.02-4.96 (4H, m), MS (ESI) m/z: 447 (M + H)⁺. Intermediate-55b ¹H-NMR (300 MHz, CDCl₃) δ 8.80 (1H, s), 8.47 (1H, d, J = 5.9 Hz), 8.35 (1H, d, J = 2.2 Hz), 7.75 (1H, d, J = 6.2 Hz), 7.32-7.23 (2H, m), 5.75 (2H, s), 4.55 (2H, q, J = 7.0 Hz), 4.47 (2H, t, J = 12.8 Hz), 1.50 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 431 (M + H)⁺. Intermediate-56b ¹H-NMR (300 MHz, CDCl₃) δ 8.66 (1H, s), 8.49 (1H, d, J = 6.2 Hz), 7.76 (1H, d, J = 6.2 Hz), 7.38 (2H, d, J = 8.8 Hz), 7.24 (2H, d, J = 8.8 Hz), 5.91 (1H, tt, J = 52.7, 2.6 Hz), 5.67 (2H, s), 4.54 (2H, q, J = 7.0 Hz), 1.49 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 398 (M + H)⁺. Intermediate-57b ¹H-NMR (300 MHz, DMSO-d₆) δ 9.05 (1H, s), 8.37-8.33 (2H, m), 7.84-7.77 (1H, m), 7.57-7.40 (2H, m), 6.68 (1H, tt, J = 52.1 and 5.1 Hz), 5.86 (2H, s), 4.70 (2H, t, J = 13.9 Hz), 4.45 (2H, q, J = 6.6 Hz), 1.41 (3H, t, J = 6.6 Hz), MS (ESI) m/z: 413 (M + H)⁺. Intermediate-58b ¹H-NMR (300 MHz, CDCl₃) δ 8.70 (1H, s), 8.49 (1H, d, J = 6.2 Hz), 8.14 (1H, d, J = 2.2 Hz), 7.76-7.74 (2H, m), 6.05 (1H, tt, J = 52.7, 4.7 Hz), 5.60 (2H, s), 4.78 (2H, t, J = 12.1 Hz), 4.55 (2H, q, J = 7.0 Hz), 1.50 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 447 (M + H)⁺. Intermediate-59b ¹H-NMR (300 MHz, CDCl₃) δ 8.69 (1H, s), 8.58 (1H, d, J = 5.9 Hz), 7.85 (1H, d, J = 6.2 Hz), 7.62 (2H, s), 7.53-7.44 (4H, m), 7.34-7.27 (3H, m), 5.73 (2H, s), MS (ESI) m/z: 398 (M + H)⁺. Intermediate-60b ¹H-NMR (300 MHz, CDCl₃) δ 8.82 (1H, s), 8.46 (1H, d, J = 6.6 Hz), 8.12 (1H, s), 7.74 (1H, d, J = 6.6 Hz), 7.12 (1H, s), 5.92 (1H, q, J = 7.4 Hz), 4.55 (2H, q, J = 7.3 Hz), 4.43 (2H, q, J = 8.0 Hz), 2.24 (3H, s), 2.10 (3H, d, J = 7.4 Hz), 1.50 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 409 (M + H)⁺. Intermediate-61b ¹H-NMR (300 MHz, CDCl₃) δ 8.66 (1H, s), 8.57 (1H, d, J = 5.9 Hz), 8.44 (1H, d, J = 2.2 Hz), 7.84 (1 H, d, J = 5.9 Hz), 7.49-7.43 (3H, m), 7.34-7.27 (3H, m), 5.64 (2H, s), 3.03-2.98 (2H, m), 2.71-2.57 (2H, m), 2.23 (3H, s), MS (ESI) m/z: 441 (M + H)⁺. Intermediate-62b MS (ESI) m/z: 409 (M + H)⁺. Table 6-5 Intermediate-63b ¹H-NMR (300 MHz, CDCl₃) δ 8.67 (1H, s), 8.58 (1H, d, J = 6.6 Hz), 8.12 (1H, s), 7.84 (1H d, J = 6.6 Hz), 7.72 (1H, d, J = 2.2 Hz), 7.47 (2H, t, J = 7.3 Hz), 7.35-7.26 (3H, m), 5.60 (2H, s), 4.54 (2H, t, J = 11.7 Hz), 1.76 (3H, t, J = 18.3 Hz), MS (ESI) m/z: 459 (M + H)⁺. Intermediate-64b ¹H-NMR (300 MHz, CDCl₃) δ 8.68 (1H, s), 8.49 (1H, d, J = 6.2 Hz), 8.13 (1H, d, J = 2.2 Hz), 7.75 (1H, d, J = 5.9 Hz), 7.70 (1H, d, J = 1.8 Hz), 5.58 (2H, s), 4.62 (2H, t, J = 6.6 Hz), 4.55 (2H, q, J = 7.0 Hz), 2.74-2.58 (2H m), 1.50 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 429 (M + H)⁺. Intermediate-65b ¹H-NMR (300 MHz, CDCl₃) δ 8.85 (1H, s), 8.48 (1H, d, J = 5.9 Hz), 8.08 (1H, s), 7.72 (1H, d, J = 6.2 Hz), 7.59 (1H, d, J = 7.3 Hz), 7.46 (1H, d, J = 8.8 Hz), 6.02 (2H, s), 4.53 (2H, q, J = 7.3 Hz), 3.96 (3H, s), 1.48 (3H, t, J = 6.9 Hz), MS (ESI) m/z: 404 (M + H)⁺. Intermediate-66b ¹H-NMR (300 MHz, CDCl₃) δ 8.78 (1H, s), 8.47 (1H, d, J = 6.0 Hz), 8.14 (1H, s), 7.75 (1H, d, J = 6.0 Hz), 7.14 (1H, s), 6.02 (1H, tt, J = 52.9, 4.0 Hz), 5.70 (2H, s), 4.55 (2H, q, J = 7.3 Hz), 4.45 (2H, t, J = 11.7 Hz), 2.23 (3H, s), 1.50 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 427 (M + H)⁺. Intermediate-67b ¹H-NMR (300 MHz, DMSO-d₆) δ 8.66 (1H, s), 8.49 (1H, d, J = 5.9 Hz), 8.11 (1H, d, J = 2.2 Hz), . 7 75 (1H, d, J = 5.9 Hz), 7.67 (1H, d, J = 2.2 Hz), 5.57 (2H, s), 4.55 (2H, q, J = 7.0 Hz), 4.23 (2H, d, J = 7.4 Hz), 1.50 (3H, t, J = 7.0 Hz), 1.38-1.20 (1H, m), 0.66-0.56 (2H, m), 0.42-0.32 (2H, m), MS (ESI) m/z: 387 (M + H)⁺. Intermediate-68b ¹H-NMR (300 MHz, CDCl₃) δ 8.83 (1H, s), 8.46 (1H, d, J = 6.6 Hz), 8.12 (1H, s), 7.75 (1H, d, J = 5.9 Hz), 7.12 (1H, s), 5.93 (1H, q, J = 6.6 Hz), 4.55 (2H, q, J = 7.3 Hz), 4.43 (2H, q, J = 7.3 Hz), 2.25 (3H, s), 2.10 (3H, d, J = 7.3 Hz), 1.50 (3H, t, J = 6.6 Hz), MS (ESI) m/z: 409 (M + H)⁺. Intermediate-69b ¹H-NMR (300 MHz, CDCl₃) δ 8.65 (1H, s), 8.49 (1H, d, J = 6.2 Hz), 7.76 (1H, d, J = 6.2 Hz), 7.43 (1H, d, J = 2.2 Hz), 7.25 (1H, dd, J = 8.4, 2.2 Hz), 6.97 (1H, d, J = 8.4 Hz), 5.59 (2H, s), 4.54 (2H, q, J = 7.1 Hz), 4.40 (2H, q, J = 8.0 Hz), 1.50 (3H, t, J = 7.1 Hz), MS (ESI) m/z: 414 (M + H)⁺. Intermediate-70b ¹H-NMR (300 MHz, CDCl₃) δ 8.63 (1H, s), 8.48 (1H, d, J = 6.2 Hz), 8.09 (1H, d, J = 2.2 Hz), 7.76 (1H, d, J = 6.2 Hz), 7.49-7.37 (3H, m), 7.10-6.98 (2H, m), 5.56 (2H, s), 5.37 (2H, s), 4.54 (2H, q, J = 6.9 Hz), 2.20 (3H, s), 1.49 (3H, t, J = 6.9 Hz), MS (ESI) m/z: 421 (M + H)⁺. Intermediate-71b ¹H-NMR (300 MHz, CDCl₃) δ 8.62 (1H, s), 8.47 (1H, d, J = 6.2 Hz), 8.04 (1H, d, J = 2.0 Hz), 7.76 (1H, d, J = 6.2 Hz), 7.38 (1H, d, J = 2.0 Hz), 5.54 (2H, s), 5.21 (1H, quintet, J = 7.0 Hz), 4.53 (2H, q, J = 7.0 Hz), 2.53-2.38 (2H, m), 2.20-2.07 (2H, m), 2.16 (3H, s), 1.94-1.60 (2H, m), 1.49 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 367 (M + H)⁺. Intermediate-72b ¹H-NMR (300 MHz, CDCl₃) δ 8.75 (1H, s), 8.46 (1H, d, J = 5.9 Hz), 8.09 (1H, s), 7.75 (1H, d, J = 5.9 Hz), 7.11 (1H, s), 5.68 (2H, s), 4.54 (2H, q, J = 7.0 Hz), 3.90 (2H, d, J = 6.6 Hz), 2.22 (3H, s), 1.49 (3H, t, J = 7.0 Hz), 1.34-1.20 (1H, m), 0.69-0.58 (2H, m), 0.40-0.30 (2H, m), MS (ESI) m/z: 367 (M + H)⁺. Intermediate-73b ¹H-NMR (300 MHz, CDCl₃) δ 8.81 (1H, s), 8.49 (1H, d, J = 5.9 Hz), 7.75 (1H, d, J = 5.9 Hz), 7.34 (1H, s), 5.99 (1H, tt, J = 53.4, 4.3 Hz), 5.89 (2H, s), 4.95 (2H, t, J = 12.5 Hz), 4.55 (2H, q, J = 7.3 Hz), 2.24 (3H, s), 1.50 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 428 (M + H)⁺. Table 6-6 Intermediate-74b ¹H-NMR (300 MHz, CDCl₃) δ 8.77 (1H, s), 8.47 (1H, d, J = 6.0 Hz), 8.11 (1H, s), 7.75 (1H, d, J = 6.0 Hz), 7.14 (1H, s), 5.70 (2H, s), 4.55 (2H, q, J = 7.0 Hz), 4.19 (2H, t, J = 11.0 Hz), 2.24 (3H, s), 1.78 (3H, t, J = 18.7 Hz), 1.50 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 391 (M + H)⁺. Intermediate-75b ¹H-NMR (300 MHz, CDCl₃) δ 8.59 (1H, s), 8.47 (1H, d, J = 6.2 Hz), 7.76 (1H, d, J = 6.2 Hz), 7.24-7.18 (2H, m), 6.78 (1H, d, J = 8.8 Hz), 5.57 (2H, s), 4.53 (2H, q, J = 7.3 Hz), 4.10 (2H, t, J = 11.0 Hz), 2.24 (3H, s), 1.79 (3H, t, J = 18.7 Hz), 1.49 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 390 (M + H)⁺. Intermediate-76b ¹H-NMR (300 MHz, CDCl₃) δ 8.61 (1H, s), 8.46 (1H, d, J = 6.0 Hz), 7.76 (1H, d, J = 6.0 Hz), 7.21-7.13 (2H, m), 6.77 (1H, d, J = 9.2 Hz), 6.09 (1H, tt, J = 55.0 and 4.0 Hz), 5.82 (1H, q, J = 6.9 Hz), 4.53 (2H, q, J = 7.3 Hz), 4.17 (2H, td, J = 13.0 and 4.0 Hz), 2.22 (3H, s), 2.06 (3H, d, J = 6.9 Hz), 1.49 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 390 (M + H)⁺. Intermediate-77b ¹H-NMR (300 MHz, CDCl₃) δ 8.64 (1H, s), 8.48 (1H, d, J = 5.9 Hz), 7.77 (1H, d, J = 5.9 Hz), 7.02 (2H, s), 6.07 (1H, tt, J = 55.0 and 4.4 Hz), 5.54 (2H, s), 4.54 (2H, q, J = 6.6 Hz), 3.99 (2H, td, J = 13.9 and 4.4 Hz), 2.27 (6H, s), 1.49 (3H, t, J = 6.6 Hz), MS (ESI) m/z: 390 (M + H)⁺. Intermediate-78b ¹H-NMR (300 MHz, CDCl₃) δ 8.62 (1H, s), 8.48 (1H, d, J = 6.2 Hz), 7.76 (1H, d, J = 5.9 Hz), 7.18 (1H, d, J = 7.3 Hz), 6.94 (1H, d, J = 7.7 Hz), 6.79 (1H, s), 6.09 (1H, tt, J = 54.9 and 4.0 Hz), 5.60 (2H, s), 4.53 (2H, q, J = 7.0 Hz), 4.14 (2H, td, J = 12.8 and 4.0 Hz), 2.23 (3H, s), 1.49 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 376 (M + H)⁺. Intermediate-79b ¹H-NMR (270 MHz, CDCl₃) δ 8.60 (1H, s), 8.46 (1H, d, J = 6.3 Hz), 7.76 (1H, d, J = 6.3 Hz), 7.22-7.14 (2H, m), 6.77 (1H, d, J = 8.9 Hz), 5.82 (1H, q, J = 6.9 Hz), 4.53 (2H, q, J = 7.2 Hz), 4.09 (2H, t, J = 11.3 Hz), 2.23 (3H, s), 2.06 (3H, d, J = 6.9 Hz), 1.78 (3H, t, J = 18.8 Hz), 1.48 (3H, t, J = 7.2 Hz), MS (ESI) m/z: 404 (M + H)⁺. Intermediate-80b ¹H-NMR (270 MHz, CDCl₃) δ 8.62 (1H, s), 8.46 (1H, d, J = 6.0 Hz), 7.76 (1H, d, J = 6.0 Hz), 7.22-7.13 (2H, m), 6.77 (1H, d, J = 9.2 Hz), 6.09 (1H, tt, J = 55.3 and 4.0 Hz), 5.82 (1H, q, J = 6.9 Hz), 4.53 (2H, q, J = 7.3 Hz), 4.17 (2H, td, J = 12.9 and 4.0 Hz), 2.22 (3H, s), 2.06 (3H, d, J = 6.9 Hz), 1.49 (3H, t, J = 7.3 Hz), MS (ESI) m/z: 390 (M + H)⁺. Intermediate-81b ¹H-NMR (270 MHz, CDCl₃) δ 8.64 (1H, s), 8.48 (1H, d, J = 5.9 Hz), 7.76 (1H, d, J = 5.9 Hz), 7.26-7.18 (2H, m), 7.08 (1H, d, J = 7.9 Hz), 6.49 (1H, t, J = 73.8 Hz), 5.60 (2H, s), 4.54 (2H, q, J = 6.6 Hz), 2.28 (3H, s), 1.49 (3H, t, J = 6.6 Hz), MS (ESI) m/z: 362 (M + H)⁺.

EXAMPLE SYNTHESIS PART

Example compounds (Example-1 to 649) are prepared as follows.

Representative Procedure for Method G

The following preparation of Example 1 represents the Method G.

Example 1 N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide

A mixture of 4-chloro-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine (20 mg, 0.056 mmol, Intermediate-1a), isopbutyramide (15 mg, 0.17 mmol), tirs(dibenzylideneacetone)dipalladium(0) (1 mg, 1 micromol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2 mg, 3 micromol), and tripotassium phosphate (18 mg, 0.084 mmol) in dioxane (2 mL) is stirred at 170° C. for 20 minutes under microwave irradiation. After cooling to rt, the resulting mixture is filtered through a short column of NH-gel eluting with EtOAc, and the filtrate is concentrated. The residue is purified by a strong cation exchange cartridge (BondElute(registered trademark) SCX, 1 g/6 mL, Varian Inc.) and then by preparative LC-MS to give 9.3 mg (40% yield) of the title compound.

Representative Procedure for Method H

The following preparation of Example 33 represents the Method H.

Example 33 N-isopropyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide

To a mixture of 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylic acid (16 mg, 0.044 mmol, Intermediate-1c) and triethylamine (0.06 mL, 0.4 mmol) in DMF (1 mL) is added HBTU (33 mg, 0.087 mmol). After stirring at rt for 10 minutes, isopropylamine (0.022 mL, 0.26 mmol) is added to the mixture. After stirring at 60° C. for 1 hour, the mixture is diluted with EtOAc (3 mL). The organic layer is washed with water (3 mL), dried over sodium sulfate, and concentrated in vacuo. The residue is filtered through NH-gel eluting with EtOAc, and the filtrate is concentrated in vacuo. The residue is purified by preparative LC-MS to give 4.6 mg (26% yield) of the title compound.

Representative Procedure for Method J

The following preparation of Example 289 represents the Method J.

Example 289 2-(2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide

A mixture of phenyl 2-(2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate (15 mg, 0.032 mmol, Intermediate-36b) and 40% aqueous methylamine solution (0.1 mL) in THF (1 mL) is stirred at 80° C. for 2 hours. After removing the solvent, the residue is purified by preparative LC-MS to give 8.6 mg (66% yield) of the title compound.

Representative Procedure for Method K

The following preparation of Example 143 represents the Method K.

Example 143 N-methyl-2-((4-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4.3-c]pyridine-4-carboxamide

A mixture of ethyl 2-((4-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate (15 mg, 0.038 mmol, Intermediate-20b) and 40% aqueous methylamine solution (2 mL) is stirred at 60° C. for 30 minutes. After cooling to rt, the mixture is diluted with EtOAc (2 mL) and washed with water (2 mL). The organic layer is dried over sodium sulfate and concentrated. The residue is purified by a strong cation exchange cartridge (BondElute(registered trademark) SCX, 1 g/6 mL, Varian Inc.) and then by preparative LC-MS to give 6.0 mg (42% yield) of the title compound.

Representative Procedure for Method L

The following preparation of Example 141 represents the Method L.

Example 141 N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide

A mixture of ethyl 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxylate (1.10 g, 2.79 mmol, Intermediate-1b) and 2-aminoethanol (3.41 g, 55.8 mmol) in EtOH (20 mL) is stirred at 60° C. for 3 hours. After evaporation of the solvent, the residue is diluted with EtOAc (200 mL) and washed with water (100 mL) and brine (100 mL). The organic layer is dried over sodium sulfate and concentrated in vacuo. The residual solid is washed with diisopropyl ether-EtOAc to give 1.13 g (99% yield) of the title compound as a white powder.

Representative Procedure for Method M

The following preparation of Example 30 represents the Method M.

Example 30 4-methoxy-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine

The title compound is prepared in 41% yield (72 mg, a yellow oil) from 4-chloro-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine (180 mg, 0.51 mmol, Intermediate-1a) using MeOH as a solvent in a similar manner to Step-2 of Intermediate-A14.

Representative Procedure for Method N

The following preparation of Example 55 represents the Method N.

Example 55 4-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)morpholine

A mixture of 4-chloro-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine (20 mg, 0.056 mmol, Intermediate-1a), morpholine (49 mg, 0.56 mmol), and potassium carbonate (47 mg, 0.34 mmol) in DMA (1.5 mL) is stirred at 120° C. for 3 hours. After cooling to rt, the mixture is diluted with EtOAc (5 mL) and washed with water (5 mL). The organic layer is dried over sodium sulfate and concentrated. The residue is purified by a strong cation exchange cartridge (BondElute(registered trademark) SCX, 1 g/6 mL, Varian Inc.) and then by preparative LC-MS to give 8.5 mg (37% yield) of the title compound.

Representative Procedure for Method P

The following preparation of Example 64 represents the Method P.

Example 64 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-4-(1H-pyrazol-5-yl)-2H-pyrazolo[4,3-c]pyridine

A mixture of 4-chloro-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine (25 mg, 0.070 mmol, Intermediate-1a), (1H-pyrazol-5-yl)boronic acid hydrate (27 mg, 0.21 mmol), tris(dibenzylideneacetone)dipalladium(0) (13 mg, 0.014 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (12 mg, 0.028 mmol), and potassium phosphate (45 mg, 0.21 mmol) in DMF (1 mL) is stirred at 100° C. for 16 hours. After cooling to rt, the mixture is diluted with EtOAc (5 mL) and washed with water (5 mL). The organic layer is dried over sodium sulfate and concentrated. The residue is purified by a strong cation exchange cartridge (BondElute(registered trademark) SCX, 1 g/6 mL, Varian Inc.) and then by preparative LC-MS to give 2.9 mg (11% yield) of the title compound.

The following examples are prepared using the Method G, H, J, K, L, M, or N from starting materials and reagents shown in Table 7-1 to 7-55 and Table 8-1 to 8-15. The retention time and observed MS (positive or negative mode) by LC-MS of all examples are described in Table 9-1 to 9-5. ¹H-NMR data of Example 1, 2, 69, 141, 149, 158, 166, 172, 174, 179, 183, 199, 220, 222, 223, 288, 301, 343, 462, and 518 are described in Table 10-1 to 10-2.

TABLE 7 Ex Structure Name  2

2-hydroxy-2-methyl-N-(2-((5-methyl-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridin- 4-yl)propanamide  3

N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)acetamide  4

N-(2-((6-(2,2-difluoroethoxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)isobutyramide  5

N-(2-((6-(2,2-difluoroethoxy)-5- methylpyridin-3-yl)methyl-2H- pyrazolo[4,3-c]pyridin-4-yl)acetamide  6

N-(2-((6-(2,2-difluoroethoxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)propionamide  7

N-(2-((6-(2,2-difluoroethoxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)cyclopropanecarboxamide  8

N-(2-((6-(2,2-difluoroethoxy)-5- methylpyridin-3-yl)methyl-2H- pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy- 2-methylpropanamide  9

N-(2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)ethyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)acetamide  10

N-(2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)ethyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)propionamide  11

N-(2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)ethyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)isobutyramide  12

N-(2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)ethyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)tetrahydro- 2H-pyran-4-carboxamide  13

N-(2-((6-(2,2,2-trifluoroethoxy)pyridin- 3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4- yl)cyclopropanecarboxamide  14

N-(2-((6-(2,2,2-trifluoroethoxy)pyridin- 3-yl)methyl)-2H-pyrazolo[4,3-c] pyridin-4-yl)isobutyramide  15

N-(2-((5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)isobutyramide  16

N-(2-((5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)propionamide  17

N-(2-((5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl) tetrahydro-2H-pyran-4-carboxamide  18

N-(2-((5-chloro-6-(2,2- difluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)acetamide  19

N-(2-((5-chloro-6-(2,2- difluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl) propionamide  20

N-(2-((5-chloro-6-(2,2- difluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl) isobutyramide  21

N-(2-((5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl)acetamide  22

N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)tetrahydro-2H-pyran-4-carboxamide  23

N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)oxazole-5-carboxamide  24

1,1-dimethyl-3-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl)urea  25

2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-amine  26

3-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)oxazolidin-2-one  27

ethyl (2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)carbamate  28

N-(2-((6-(2,2,2-trifluoroethoxy)pyridin- 3-yl)methyl)-2H-pyrazolo[4,3-c] pyridin-4-yl)acetamide  29

N-(2-((6-(2,2,2-trifluoroethoxy)pyridin- 3-yl)methyl)-2H-pyrazolo[4,3-c] pyridin-4-yl)propionamide  31

2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide  32

N-methyl-2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide  34

N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)cyclopropanecarboxamide  35

N-(2-((6-(2,2-difluoroethoxy)-5- fluoropyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)cyclopropanecarboxamide  36

N-(2-((6-(2,2-difluoroethoxy)-5- fluoropyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)isobutyramide  37

N-(2-((6-(2,2,2- trifluoroethoxy)pyridazin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)isobutyramide  38

N-(2-((6-(2,2,2- trifluoroethoxy)pyridazin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)cyclopropanecarboxamide  39

N-(2-((5-(2,2,2-trifluoroethoxy)pyridin- 2-yl)methyl)-2H-pyrazolo[4,3-c] pyridin-4-yl)isobutyramide  40

N-(2-((5-(2,2,2-trifluoroethoxy)pyridin- 2-yl)methyl)-2H-pyrazolo[4,3-c] pyridin-4-yl)cyclopropanecarboxamide  41

N-(2-((6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)isobutyramide  42

N-(2-((6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)cyclopropanecarboxamide  43

N-(2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)ethyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)isobutyramide (single enantiomer)  44

N-(2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)ethyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)cyclopropanecarboxamide (single enantiomer)  45

N-(2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)ethyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)acetamide (single enantiomer)  46

N-(2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)ethyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)propionamide (single enantiomer)  47

N-(2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)ethyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)tetrahydro- 2H-pyran-4-carboxamide (single enantiomer)  48

N-(2-((5-fluoro-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)propionamide  49

N-(2-((5-fluoro-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)cyclopropanecarboxamide  50

N-(2-((5-fluoro-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)isobutyramide  51

N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)pivalamide  52

N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)nicotinamide  53

1-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)pyrrolidin-2-one  54

1-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)imidazolidin-2-one  56

N-(1-methyl-1H-pyrazol-3-yl)-2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-amine  57

2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- (pyrimidin-2-yl)-2H-pyrazolo[4,3-c] pyridin-4-amine  58

N-(2-((6-(2,2,3,3- tetrahydropropoxy)pyridin-3- yl)methyl-2H-pyrazolo[4,3-c]pyridin- 4-yl)cyclopropanecarboxamide  59

N-(2-((6-(2,2-difluoroethoxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)tetrahydro- 2H-pyran-4-carboxamide  60

3-(2-((6-(2,2-difluoroethoxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)-1,1- dimethylurea  61

N-(2-((6-(2,2-difluoroethoxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)pivalamide  62

N-(2-(4-(2,2,2-trifluoroethoxy)benzyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)isobutyramide  63

N-(2-(4-(2,2,2-trifluoroethoxy)benzyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)cyclopropanecarboxamide  65

N-(2-((6-(2,2,3,3,3- pentafluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide  66

N-(2-((6-(2,2,3,3,3- pentafluoropropoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl) cyclopropanecarboxamide  67

N-(2-(4-(trifluoromethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)isobutyramide  68

2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)ethyl)-2H- pyrazolo[4,3-c]pyridine-4- carboxamide (single enantiomer)  69

N-ethyl-2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide  70

(S)-2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- (tetrahydrofuran-3-yl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide  71

N-cyclopropyl-2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide  72

N-cyclobutyl-2-((5-methoxy-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide  73

N-(cyclopropylmethyl)-2-((5-methyl-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide  74

2-((5-methyl-6-(2,2,2-trifluoroethoxy) pyridin-3-yl)methyl)-N-((tetrahydro-2H- pyran-4-yl)methyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide  75

N-(2-methoxyethyl)-2-((5-methyl-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide  76

(R)-N-(1-hydroxypropan-2-yl)-2-((5- methyl-6-(2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide  77

N-(3-methyl-2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl) propionamide  78

N-(3-methyl-2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl) cyclopropanecarboxamide  79

N-(2-((6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)isobutyramide  80

N-(2-(1-(6-(2,2-difluoroethoxy)-5- methylpyridin-3-yl)ethyl)-2H- pyrazolo[4,3-c]pyridin-4-yl) cyclopropanecarboxamide (single enantiomer)  81

N-(2-(2-(6-(2,2,2- trifluoroethoxy)pyridin-3-yl)ethyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)cyclopropanecarboxamide  82

N-(2-((6-(4-fluorophenoxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)isobutyramide  83

N-(2-((6-(4-fluorophenoxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)cyclopropanecarboxamide  84

N-methyl-N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)isobutyramide  85

(S)-N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)tetrahydrofuran-2-carboxamide  86

(S)-N-(2-((6-(2,2-difluoroethoxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)tetrahydrofuran-2-carboxamide  87

N-(2-((6-(2,2-difluoroethoxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)nicotinamide  88

(R)-2-hydroxy-N-(2-((5-methyl-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl) propanamide  89

(S)-2-hydroxy-N-(2-((5-methyl-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridin- 4-yl)propanamide  90

N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)pyrrolidine-1-carboxamide  91

1-acetyl-N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)piperidine-4-carboxamide  92

N-isopropyl-2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)ethyl)-2H- pyrazolo[4,3-c]pyridine-4- carboxamide (single enantiomer)  93

2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- propyl-2H-pyrazolo[4,3-c]pyridine-4- carboxamide  94

N-isobutyl-2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide  95

N-(2-ethoxyethyl)-2-((5-methyl-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide  96

N-(cyanomethyl)-2-((5-methyl)-6- (2,2,2-trifluoroethoxy)pyridin-3-yl) methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide  97

(S)-2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- ((tetrahydrofuran-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide  98

N-(2-(dimethylamino)ethyl)-2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide  99

2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- (pyridin-3-ylmethyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 100

N-((5-methyl-1,2,4-oxadiazol-3- yl)methyl)-2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 101

2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- (pyridin-3-yl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 102

(R)-N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)tetrahydrofuran-2-carboxamide 103

(R)-N-(2-((6-(2,2-difluoroethoxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)tetrahydrofuran-2-carboxamide 104

N-(3-methoxypropyl)-2-((5-methyl-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 105

N-((1-hydroxycyclohexyl)methyl)-2- ((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 106

N-(6-methyl-2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)propionamide 107

N-(6-methyl-2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)cyclopropanecarboxamide 108

N-(6-methyl-2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)isobutyramide 109

2-hydroxy-2-methyl-N-(6-methyl-2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)propanamide 110

N-(7-methyl-2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl) propionamide 111

N-(7-methyl-2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)isobutyramide 112

2-((6-(2,2-difluoroethoxy)-5- methylpyridin-3-yl)methyl)-N-ethyl- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 113

2-((6-(2,2-difluoroethoxy)-5- methylpyridin-3-yl)methyl)-N-methyl- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 114

1-isobutyryl-N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)piperidine-4-carboxamide 115

N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl)-1- (methylsulfonyl)piperidine-4-carboxamide 116

(S)-1-acetyl-N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl)-1- (methylsulfonyl)piperidine-4- carboxamide 117

(R)-1-acetyl-N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)pyrrolidine-2-carboxamide 118

N-methyl-N-(2-((2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl)amino)- 2-oxoethyl)acetamide 119

(S)-2-methoxy-N-(2-((5-methyl-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridin- 4-yl)propanamide 120

(S)-N-(2-((6-(2,2-difluoroethoxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)-2- methoxypropanamide 121

(R)-N-(2-((6-(2,2-difluoroethoxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)-2- hydroxypropanamide 122

(S)-N-(2-((6-(2,2-difluoroethoxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)-2- hydroxypropanamide 123

2-((6-(2,2-difluoroethoxy)-5- methylpyridin-3-yl)methyl)-N- isopropyl-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 124

N-cyclopropyl-2-((6-(2,2- difluoroethoxy)-5-methylpyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 125

N-(cyclopropylmethyl)-2-((6-(2,2- difluoroethoxy)-5-methylpyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 126

2-((6-(2,2-difluoroethoxy)-5- methylpyridin-3-yl)methyl)-N-(2- (dimethylamino)ethyl)-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 127

2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- (2-morpholinoethyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 128

N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl)-2- (pyridin-2-yl)acetamide 129

N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl)-2- (pyridin-3-yl)acetamide 130

N-isopropyl-2-((6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 131

N-ethyl-2-((6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 132

N-cyclopropyl-2-((6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 133

N-(cyclopropylmethyl)-2-((6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 134

N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl)-2- (pyridin-4-yl)acetamide 135

N-(cyanomethyl)-2-((6-(2,2- difluoroethoxy)-5-methylpyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 136

2-((6-(2,2-difluoroethoxy)-5- methylpyridin-3-yl)methyl)-N-propyl- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 137

N-(2-cyanopropan-2-yl)-2-((5-methyl- 6-(2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 138

N-(2-hydroxy-2-methylpropyl)-2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 139

N-(3-(dimethylamino)propyl)-2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 140

N-(2-aminoethyl)-2-((5-methyl-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 142

2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- (oxetan-3-yl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 144

N-ethyl-2-((4-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 145

N-(2-((6-(2,2-difluoroethoxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)-2-(pyridin- 4-yl)acetamide 146

2-(pyridin-4-yl)-N-(2-((6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl)acetamide 147

N-(2-((6-(2,2-difluoroethoxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)-2-(pyridin- 3-yl)acetamide 148

2-((6-(2,2-difluoroethoxy)-5- methylpyridin-3-yl)methyl)-N-(2- hydroxyethyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 149

N-(2-hydroxyethyl)-2-((5-methyl-6- (3,3,3-trifluoropropoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 150

N-(2-hydroxyethyl)-2-((4-methyl-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 151

N-(2-((5-methyl-6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl) isobutyramide 152

N-(2-((5-methyl-6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl) cyclopropanecarboxamide 153

2-hydroxy-2-methyl-N-(2-((5-methyl-6- (3,3,3-trifluoropropoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridin- 4-yl)propanamide 154

N-methyl-2-((5-methyl-6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 155

N-ethyl-2-((5-methyl-6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 156

N-isopropyl-2-((5-methyl-6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 157

N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridazin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)isobutyramide 158

N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridazin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)cyclopropanecarboxamide 159

N-methyl-2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridazin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 160

N-ethyl-2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridazin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 161

N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl)-2-(2- methylthiazol-4-yl)acetamide 162

N-(2-((5-methyl-6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl)-2- (pyridin-3-yl)acetamide 163

N-(2-((5-methyl-6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl)-2- (pyridin-4-yl)acetamide 164

2-(3,5-dimethylisoxazol-4-yl)-N-(2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)acetamide 165

N-isopropyl-2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridazin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 166

(R)-N-(2-hydroxypropyl)-2-((5-methyl- 6-(2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 167

(S)-N-(2-hydroxypropyl)-2-((5-methyl- 6-(2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 168

(S)-N-(2,3-dihydroxypropyl)-2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 169

N-(2-((4-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)cyclopropanecarboxamide 170

2-hydroxy-2-methyl-N-(2-((4-methyl-5- (2,2,2-trifluoroethoxy)pyridin-2- yl)methyl)-2H-pyrazolo[4,3-c]pyridin- 4-yl)propanamide 171

N-methyl-2-((4-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 172

N-ethyl-2-((4-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 173

N-isopropyl-2-((4-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 174

N-(2-hydroxyethyl)-2-((4-methyl-5- (2,2,2-trifluoroethoxy)pyridin-2- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 175

(S)-N-(1-hydroxypropan-2-yl)-2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 176

N-(2-amino-2-oxoethyl)-2-((5-methyl- 6-(2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 177

2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- (2-(methylsulfonamido)ethyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 178

N-(2-hydroxyethyl)-2-((5-methyl-6- (2,2,2-trifluoroethoxy)pyridazin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 179

N-(3-hydroxypropyl)-2-((5-methyl-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 180

2-((6-(2,2-difluoroethoxy)-5- methylpyridin-3-yl)methyl)-N-(3- hydroxypropyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 181

N-(2-cyanoethyl)-2-((5-methyl-6- (2,2,2-trifluoroethoxy)pyridin-3-yl) methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 182

N-(2-cyanoethyl)-2-((6-(2,2- difluoroethoxy)-5-methylpyridin-2- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 183

N-(2-acetamidoethyl)-2-((5-methyl-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 184

N-(2-((5-methoxy-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)isobutyramide 185

N-(2-((5-methoxy-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)cyclopropanecarboxamide 186

2-((5-methoxy-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- methyl-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 187

N-ethyl-2-((5-methoxy-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 188

N-isopropyl-2-((5-methoxy-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 189

N-(2-hydroxyethyl)-2-((5-methoxy-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 190

N-(2-(2-hydroxyethoxy)ethyl)-2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 191

N-(2-((4-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)isobutyramide 192

N-ethyl-2-((5-fluoro-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 193

2-((5-fluoro-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- isopropyl-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 194

2-((5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- (2-hydroxyethyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 195

2-((5-chloro-6-(2,2- difluoroethoxy)pyridin-3-yl)methyl)-N- methyl-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 196

2-((5-chloro-6-(2,2- difluoroethoxy)pyridin-3-yl)methyl)-N- ethyl-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 197

2-((5-chloro-6-(2,2- difluoroethoxy)pyridin-3-yl)methyl)-N- (2-hydroxyethyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 198

2-((5-chloro-6-(2,2- difluoroethoxy)pyridin-3-yl)methyl)-N- isopropyl-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 199

(R)-N-(2,3-dihydroxypropyl)-2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 200

N-(2-hydroxyethyl)-2-(4-(2,2,2- trifluoroethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 201

2-((6-(4-fluorophenoxy)-5- methylpyridin-3-yl)methyl)-N-(2- hydroxyethyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 202

N-(2-hydroxyethyl)-2-((6-(2,2,3,3,3- pentafluoropropoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 203

N-methyl-2-((6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 204

N-ethyl-2-((6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 205

N-isopropyl-2-((6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 206

N-(2-hydroxyethyl)-2-((6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 207

(S)-N-(1-amino-1-oxopropan-2-yl)-2- ((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 208

2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- (2-(methylamino)-2-oxoethyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 209

N-(3-amino-3-oxopropyl)-2-((5-methyl- 6-(2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 210

N-(3-hydroxy-2,2-dimethylpropyl)-2- ((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 211

N-(2-hydroxyethyl)-2-((6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 212

N-(4-hydroxybutyl)-2-((5-methyl-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 213

N-(3-hydroxypropyl)-2-((6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 214

N-(2-hydroxyethyl)-2-(3-methyl-4- (2,2,2-trifluoroethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 215

N-ethyl-2-((6-(2,2,3,3- tetrafluoropropoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 216

N-(2-hydroxyethyl)-2-((6-(2,2,3,3- tetrafluoropropoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 217

N-(3-acetamidopropyl)-2-((5-methyl-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 218

2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- (3-(methylsulfonamido)propyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 219

N-isopropyl-2-((6-(2,2,3,3- tetrafluoropropoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 220

2-(4-(2,2-difluoroethoxy)-3- methylbenzyl)-N-(2-hydroxyethyl)-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 221

2-(4-(2,2-difluoroethoxy)-3- methylbenzyl)-N-(3-hydroxypropyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 222

N-(2-hydroxyethyl)-2-((5-methyl-6- (2,2,3,3-tetrafluoropropoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 223

N-(3-hydroxypropyl)-2-((5-methyl-6- (2,2,3,3-tetrafluoropropoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 224

2-((5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- (3-hydroxypropyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 225

2-((5-chloro-6-(2,2- difluoroethoxy)pyridin-3-yl)methyl)-N- (3-hydroxypropyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 226

N-(3-hydroxypropyl)-2-(4-(2,2,2- trifluoroethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 227

N-(2-((2-methyl-6-(2,2,2- trifluoroethoxy)pyridin-4-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)isobutyramide 228

N-(2-((2-methyl-6-(2,2,2- trifluoroethoxy)pyridin-4-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl) cyclopropanecarboxamide 229

N-(3-hydroxypropyl)-2-(3-methyl-4- (2,2,2-trifluoroethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 230

N-(3-hydroxypropyl)-2-((5-methyl-6- (3,3,3-trifluoropropoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 231

N-(3-hydroxypropyl)-2-((5-methyl-6- (2,2,2-trifluoroethoxy)pyridazin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 232

N-(3-hydroxypropyl)-2-((4-methyl-5- (2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 233

N-(3-hydroxypropyl)-2-((5-methoxy-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 234

2-((5-fluoro-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- (3-hydroxypropyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 235

2-((6-(4-fluorophenoxy)-5- methylpyridin-3-yl)methyl)-N-(3- hydroxypropyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 236

N-(3-hydroxypropyl)-2-((6-(2,2,3,3,3- pentafluoropropoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 237

N-(3-hydroxypropyl)-2-((6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 238

N-methyl-2-((2-methyl-6-(2,2,2- trifluoroethoxy)pyridin-4-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 239

N-ethyl-2-((2-methyl-6-(2,2,2- trifluoroethoxy)pyridin-4-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 240

N-isopropyl-2-((2-methyl-6-(2,2,2- trifluoroethoxy)pyridin-4-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 241

N-(2-hydroxyethyl)-2-((2-methyl-6- (2,2,2-trifluoroethoxy)pyridin-4- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 242

N-(3-hydroxypropyl)-2-((2-methyl-6- (2,2,2-trifluoroethoxy)pyridin-4- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 243

N-(2-((6-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)isobutyramide 244

N-(2-((6-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)cyclopropanecarboxamide 245

(S)-N-(2-hydroxypropyl)-2-((5-methyl- 6-(3,3,3-trifluoropropoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 246

(R)-N-(2-hydroxypropyl)-2-((5-methyl- 6-(3,3,3-trifluoropropoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 247

(S)-N-(2,3-dihydroxypropyl)-2-((5- methyl-6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 248

(R)-N-(2,3-dihydroxypropyl)-2-((5- methyl-6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 249

(S)-N-(2,3-dihydroxypropyl)-2-((4- methyl-5-(2,2,2- trifluoroethoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 250

N-isopropyl-2-((1-(5- (trifluoromethyl)pyridin-2-yl)-1H- pyrazol-3-yl)methyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 251

N-(2-hydroxyethyl)-2-((1-(5- (trifluoromethyl)pyridin-2-yl)-1H- pyrazol-3-yl)methyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 252

N-(3-hydroxypropyl)-2-((1-(5- (trifluoromethyl)pyridin-2-yl)-1H- pyrazol-3-yl)methyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 253

N-methyl-2-((1-(5- (trifluoromethyl)pyridin-2-yl)-1H- pyrazol-3-yl)methyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 254

N-ethyl-2-((1-(5- (trifluoromethyl)pyridin-2-yl)-1H- pyrazol-3-yl)methyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 255

(S)-N-(2-hydroxypropyl)-2-((4-methyl- 5-(2,2,2-trifluoroethoxy)pyridin-2- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 256

(R)-N-(2-hydroxypropyl)-2-((4-methyl- 5-(2,2,2-trifluoroethoxy)pyridin-2- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 257

(S)-N-(1-hydroxypropan-2-yl)-2-((5- methyl-6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 258

(S)-N-(1-hydroxypropan-2-yl)-2-((4- methyl-5-(2,2,2- trifluoroethoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 259

N-(2-cyanoethyl)-2-((4-methyl-5- (2,2,2-trifluoroethoxy)pyridin-2- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 260

N-(2-cyanoethyl)-2-((5-methyl-6- (3,3,3-trifluoropropoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 261

N-(2-acetamidoethyl)-2-((5-methyl-6- (3,3,3-trifluoropropoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 262

N-(2-amino-2-oxoethyl)-2-((5-methyl- 6-(3,3,3-trifluoropropoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 263

N-(2-methoxyethyl)-2-((5-methyl-6- (3,3,3-trifluoropropoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 264

N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)ethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4- yl)isobutyramide 265

N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)ethoxy)pyridin-3-yl) methyl)-2H-pyrazolo[4,3-c]pyridin-4- yl)cyclopropanecarboxamide 266

2-hydroxy-2-methyl-N-(2-((5-methyl-6- (2-(2,2,2- trifluoroethoxy)ethoxy)pyridin-3-yl) methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl) propanamide 267

N-(2-((2-methoxy-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl) isobutyramide 268

N-(2-((2-methoxy-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl) cyclopropanecarboxamide 269

N-(2-hydroxyethyl)-2-((5-methyl-6-(2- (2,2,2-trifluoroethoxy)ethoxy)pyridin- 3-yl)methyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 270

N-(3-hydroxypropyl)-2-((5-methyl-6- (2-(2,2,2- trifluoroethoxy)ethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 271

N-methyl-2-((5-methyl-6-(2-(2,2,2- trifluoroethoxy)ethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 272

N-ethyl-2-((5-methyl-6-(2-(2,2,2- trifluoroethoxy)ethoxy)pyridin-3-yl) methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 273

N-(2-hydroxyethyl)-2-((2-methoxy-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 274

N-(3-hydroxypropyl)-2-((2-methoxy-6- (2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 275

2-((2-methoxy-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- methyl-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 276

N-ethyl-2-((2-methoxy-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 277

N-isopropyl-2-((5-methyl-6-(2-(2,2,2- trifluoroethoxy)ethoxy)pyridin-3-yl) methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 278

N-isopropyl-2-((2-methoxy-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 279

N-methyl-2-(2-(4- (trifluoromethyl)phenoxy)ethyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 280

N-ethyl-2-(2-(4- (trifluoromethyl)phenoxy)ethyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 281

N-isopropyl-2-(2-(4- (trifluoromethyl)phenoxy)ethyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 282

N-(2-hydroxyethyl)-2-(2-(4- (tifluoromethyl)phenoxy)ethyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 283

N-(3-hydroxypropyl)-2-(2-(4- (trifluoromethyl)phenoxy)ethyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 284

N-(2-((6-methyl-5-(2,2,2- trifluoroethoxy)pyrazin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)isobutyramide 285

N-(2-((6-methyl-5-(2,2,2- trifluoroethoxy)pyrazin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl) cyclopropanecarboxamide 286

N-(2-((6-(2,2-difluoropropoxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)isobutyramide 287

N-(2-((6-(2,2-difluoropropoxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl) cyclopropanecarboxamide 288

N-(2-((6-(2,2-difluoropropoxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy- 2-methylpropanamide 290

2-(2-((3-chloro-5- (trifluoromethyl)pyridin-2-yl)oxy)ethyl)-N- ethyl-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 291

2-(2-((3-chloro-5- (trifluoromethyl)pyridin-2-yl)oxy)ethyl)-N- isopropyl-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 292

2-(2-((3-chloro-5- (trifluoromethyl)pyridin-2- yl)oxy)ethyl)-N-(2-hydroxyethyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 293

2-(2-((3-chloro-5- (trifluoromethyl)pyridin-2-yl)oxy)ethyl)-N- (3-hydroxypropyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 294

2-((5-cyclopropyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- methyl-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 295

2-((5-cyclopropyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- ethyl-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 296

2-((5-cyclopropyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- isopropyl-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 297

2-((5-cyclopropyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- (2-hydroxyethyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 298

2-((5-cyclopropyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- (3-hydroxypropyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 299

2-((6-(2,2-difluoropropoxy)-5- methylpyridin-3-yl)methyl)-N-methyl- 2-pyrazolo[4,3-c]pyridine-4-carboxamide 300

2-((6-(2,2-difluoropropoxy)-5- methylpyridin-3-yl)methyl)-N-ethyl- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 301

2-((6-(2,2-difluoropropoxy)-5- methylpyridin-3-yl)methyl)-N-(2- hydroxyethyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 302

2-((6-(2,2-difluoropropoxy)-5- methylpyridin-3-yl)methyl)-N-(3- hydroxypropyl)-2H-pyrazolo[4,3-c] 4-carboxamide 303

N-methyl-2-((6-methyl-5-(2,2,2- trifluoroethoxy)pyrazin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 304

N-ethyl-2-((6-methyl-5-(2,2,2- trifluoroethoxy)pyrazin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 305

N-(3-hydroxypropyl)-2-((6-methyl-5- (2,2,2-trifluoroethoxy)pyrazin-2- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 306

2-((6-(2,2-difluoropropoxy)-5- methylpyridin-3-yl)methyl)-N-isopropyl- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 307

N-isopropyl-2-((6-methyl-5-(2,2,2- trifluoroethoxy)pyrazin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 308

2-((6-(4-chloro-1H-pyrazol-1-yl)-5- methylpyridin-3-yl)methyl)-N-methyl- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 309

2-((6-(4-chloro-1H-pyrazol-1-yl)-5- methylpyridin-3-yl)methyl)-N-ethyl- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 310

N-(2-hydroxyethyl)-2-(1-(5-methyl-6- (2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide (single enantiomer) 311

N-(3-hydroxypropyl)-2-(1-(5-methyl-6- (2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide (single enantiomer) 312

N-methyl-2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)ethyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide (single enantiomer) 313

N-ethyl-2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)ethyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide (single enantiomer) 314

N-(2-hydroxyethyl)-2-(1-(5-methyl-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide (single enantiomer) 315

N-(3-hydroxypropyl)-2-(1-(5-methyl-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide (single enantiomer) 316

N-methyl-2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)ethyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide (single enantiomer) 317

N-ethyl-2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)ethyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide (single enantiomer) 318

N-methyl-2-((5-methyl-2-phenyl-2H- 1,2,3-triazol-4-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 319

N-(2-methoxyethyl)-2-((4-methyl-5- (2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 320

2-((6-(4-chloro-1H-pyrazol-1-yl)-5- methylpyridin-3-yl)methyl)-N- isopropyl-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 321

2-((6-(4-chloro-1H-pyrazol-1-yl)-5- methylpyridin-3-yl)methyl)-N-(2- hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 322

N-(2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)ethyl)-2H- pyrazolo[4,3-c]pyridin-4-yl) isobutyramide (single enantiomer) 323

2-hydroxy-2-methyl-N-(2-(1-(5-methyl- 6-(2,2,2-trifluoroethoxy)pyridin-3-yl) ethyl)-2H-pyrazolo[4,3-c]pyridin-4- yl)propanamide (single enantiomer) 324

N-(2-((5-methyl-2-phenyl-2H-1,2,3- triazol-4-yl)methyl)-2H-pyrazolo[4,3-c] pyridin-4-yl)cyclopropanecarboxamide 325

N-(2-((6-(2,2,2-trifluoroethoxy)pyridin- 2-yl)methyl)-2H-pyrazolo[4,3-c] pyridin-4-yl)isobutyramide 326

N-(2-((6-(2,2,2-trifluoroethoxy)pyridin- 2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4- yl)cyclopropanecarboxamide 327

N-(2-((6-(cyclopropylmethoxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)isobutyramide 328

N-(2-((6-(cyclopropylmethoxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl) cyclopropanecarboxamide 329

N-(2-((6-(cyclopropylmethoxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy- 2-methylpropanamide 330

N,6-dimethyl-2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 331

N-ethyl-6-methyl-2-((5-methyl-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 332

N-ethyl-2-((5-methyl-6-(2,2,2- trifluoroethyl)amino)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 333

N-isopropyl-2-((5-methyl-6-((2,2,2- trifluoroethyl)amino)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 334

N-(2-hydroxyethyl)-2-((5-methyl-6- ((2,2,2-trifluoroethyl)amino)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 335

N-(3-hydroxypropyl)-2-((5-methyl-6- ((2,2,2-trifluoroethyl)amino)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 336

2-((6-(cyclopropylmethoxy)-5- methylpyridin-3-yl)methyl)-N-isopropyl-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 337

N-methyl-2-((6-(2,2,2- trifluoroethoxy)pyridin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 338

N-ethyl-2-((6-(2,2,2- trifluoroethoxy)pyridin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 339

N-(2-hydroxyethyl)-2-((6-(2,2,2- trifluoroethoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 340

N-(3-hydroxypropyl)-2-((6-(2,2,2- trifluoroethoxy)pyridin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 341

2-((6-(cyclopropylmethoxy)-5- methylpyridin-3-yl)methyl)-N-methyl-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 342

2-((6-(cyclopropylmethoxy)-5- methylpyridin-3-yl)methyl)-N-ethyl- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 343

2-((6-(cyclopropylmethoxy)-5- methylpyridin-3-yl)methyl)-N-(2- hydroxyethyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 344

2-((6-(cyclopropylmethoxy)-5- methylpyridin-3-yl)methyl)-N-(3- hydroxypropyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 345

N-ethyl-2-(3-methyl-4- (trifluoromethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 346

N-isopropyl-2-(3-methyl-4- (trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 347

N-(2-hydroxyethyl)-2-(3-methyl-4- (trifluoromethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 348

N-(3-hydroxypropyl)-2-(3-methyl-4- (trifluoromethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 349

N-ethyl-2-((2-(2,2,2- trifluoroethoxy)pyridin-4-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 350

N-(2-((5-phenyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl) cyclopropanecarboxamide 351

N-methyl-2-(3-methyl-4- (trifluoromethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 352

2-((6-(4-chloro-1H-pyrazol-1-yl)-5- methylpyridin-3-yl)methyl)-N-(3- hydroxypropyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 353

N-isopropyl-2-((2-(2,2,2- trifluoroethoxy)pyridin-4-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 354

2-((6-(4-fluorophenoxy)-5- methylpyridin-3-yl)methyl)-N-methyl- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 355

N-ethyl-2-((6-(4-fluorophenoxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 356

N-(2-hydroxyethyl)-6-methyl-2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 357

N-(3-hydroxypropyl)-6-methyl-2-((5- methyl-6-(2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 358

2-((5-methyl-6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)-N-(3- (methylsulfonyl)propyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 359

N-methyl-2-((1-(2,2,2- trifluoroethoxy)isoquinolin-4-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 360

N-ethyl-2-((1-(2,2,2- trifluoroethoxy)isoquinolin-4-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 361

N-isopropyl-2-((1-(2,2,2- trifluoroethoxy)isoquinolin-4-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 362

N-(2-hydroxyethyl)-2-((1-(2,2,2- trifluoroethoxy)isoquinolin-4-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 363

N-(3-hydroxypropyl)-2-((1-(2,2,2- trifluoroethoxy)isoquinolin-4- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 364

N-ethyl-2-(4-((2,2,2- trifluoroethoxy)methyl)benzyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 365

N-(3-hydroxypropyl)-2-(4-((2,2,2- trifluoroethoxy)methyl)benzyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 366

N-isopropyl-2-(4-((2,2,2- trifluoroethoxy)methyl)benzyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 367

(S)-4-hydroxy-1-(2-((5-methyl-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridin- 4-yl)pyrrolidin-2-one 368

2-((5-(2,2-difluoroethoxy)-4- methylpyridin-2-yl)methyl)-N-(2- hydroxyethyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 369

2-((5-(2,2-difluoroethoxy)-4- methylpyridin-2-yl)methyl)-N-(3- hydroxypropyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 370

N-methyl-2-((1-methyl-5- (trifluoromethoxy)-1H-indol-2- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 371

N-ethyl-2-((1-methyl-5- (trifluoromethoxy)-1H-indol-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 372

N-isopropyl-2-((1-methyl-5- (trifluoromethoxy)-1H-indol-2- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 373

N-(2-hydroxyethyl)-2-((1-methyl-5- (trifluoromethoxy)-1H-indol-2- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 374

2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N- (2-hydroxyethyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 375

2-(3-chloro-4-(2,2- difluoroethoxy)benzyl)-N-(3- hydroxypropyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 376

N-(2-((5-methyl-6-((2,2,2- trifluoroethoxy)methyl)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4- yl)isobutyramide 377

2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- (3-(methysulfonyl)propyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 378

N-ethyl-2-((5-methyl-6-((2,2,2- trifluoroethoxy)methyl)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 379

N-isopropyl-2-((5-methyl-6-((2,2,2- trifluoroethoxy)methyl)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 380

N-(2-hydroxyethyl)-2-((5-methyl-6- ((2,2,2-trifluoroethoxy)methyl)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 381

N-(3-hydroxypropyl)-2-((5-methyl-6- ((2,2,2-trifluoroethoxy)methyl)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 382

N-(3-hydroxypropyl)-2-((1-methyl-5- (trifluoromethoxy)-1H-indol-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 383

N-(2-((5-methyl-6-((2,2,2- trifluoroethoxy)methyl)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- yl)cyclopropanecarboxamide 384

N-(2-((5-(2,2-difluoroethoxy)-4- methylpyridin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)isobutyramide 385

N-(2-((5-(2,2-difluoroethoxy)-4- methylpyridin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl) cyclopropanecarboxamide 386

N-(2-((5-(2,2-difluoroethoxy)-4- methylpyridin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy- 2-methylpropanamide 387

N-(2-(3-(trifluoromethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridin-4-yl) cyclopropanecarboxamide 388

N-(2-(3-(trifluoromethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)isobutyramide 389

2-hydroxy-2-methyl-N-(2-(3- (trifluoromethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)propanamide 390

N-(2-(2-((3-fluoro-5- (trifluoromethyl)pyridin-2-yl)oxy)ethyl)-2H- pyrazolo[4,3-c]pyridin-4-yl) cyclopropanecarboxamide 391

N-(2-(2-((3-fluoro-5- (trifluoromethyl)pyridin-2- yl)oxy)ethyl)-2H-pyrazolo[4,3-c]pyridin-4- yl)isobutyramide 392

N-methyl-2-(3- (trifluoromethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 393

N-isopropyl-2-(3- (trifluoromethoxy)benzyl)-2H-pyrazolo [4,3-c]pyridine-4-carboxamide 394

N-(2-hydroxyethyl)-2-(3- (trifluoromethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 395

N-(3-hydroxypropyl)-2-(3- (trifluoromethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 396

N-ethyl-2-(2-((3-fluoro-5- (trifluoromethyl)pyridin-2-yl)oxy)ethyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 397

2-(2-((3-fluoro-5- (trifluoromethyl)pyridin-2-yl)oxy)ethyl)-N- isopropyl-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 398

2-(2-((3-fluoro-5- (trifluoromethyl)pyridin-2-yl)oxy)ethyl)-N- (3-hydroxypropyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 399

N-(2-((5-(2,2,3,3,3- pentafluoropropoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl) isobutyramide 400

N-(2-((5-(2,2,3,3,3- pentafluoropropoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl) cyclopropanecarboxamide 401

N-(2-hydroxyethyl)-2-(4-(1,1,2,2- tetrafluoroethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 402

N-(3-hydroxypropyl)-2-(4-(1,1,2,2- tetrafluoroethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 403

N-ethyl-2-((5-(2,2,3,3,3- pentafluoropropoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 404

N-isopropyl-2-((5-(2,2,3,3,3- pentafluoropropoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 405

N-(3-hydroxypropyl)-2-((5-(2,2,3,3,3- pentafluoropropoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 406

2-((5-(2,2-difluoroethoxy)-4- methylpyridin-2-yl)methyl)-N-isopropyl-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 407

2-((5-(2,2-difluoroethoxy)-4- methylpyridin-2-yl)methyl)-N-methyl- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 408

2-((5-(2,2-difluoroethoxy)-4- methylpyridin-2-yl)methyl)-N-ethyl- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 409

N-ethyl-2-((5-(2,2,3,3- tetrafluoropropoxy)pyridin-2- yl)methyl)-2-pyrazolo[4,3-c]pyridine-4- carboxamide 410

N-(2-hydroxyethyl)-2-((5-(2,2,3,3- tetrafluoropropoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 411

N-(3-hydroxypropyl)-2-((5-(2,2,3,3- tetrafluoropropoxy)pyridin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 412

N-(2-((5-chloro-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)isobutyramide 413

N-(2-((5-chloro-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl) cyclopropanecarboxamide 414

N-(2-((5-chloro-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2- methylpropanamide 415

N-(2-((5-(2,2,3,3- tetrafluoropropoxy)pyridin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)isobutyramide 416

N-(2-acetamidoethyl)-2-((5-methyl-6- (2,2,3,3-tetrafluoropropoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 417

(S)-N-(2-hydroxypropyl)-2-((5-methyl- 6-(2,2,3,3-tetrafluoropropoxy)pyridin- 3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 418

(S)-N-(2,3-dihydroxypropyl)-2-((5- methyl-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 419

N-(2-(3-(trifluoromethyl)benzyl)-2H- pyrazolo[4,3-c]pyridin-4-yl) cyclopropanecarboxamide 420

N-(2-(3-(trifluoromethyl)benzyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)isobutyramide 421

N-methyl-2-(3- (trifluoromethyl)benzyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 422

N-ethyl-2-(3-(trifluoromethyl)benzyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 423

N-isopropyl-2-(3- (trifluoromethyl)benzyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 424

N-(3-hydroxypropyl)-2-(3- (trifluoromethyl)benzyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 425

(R)-N-(2-hydroxypropyl)-2-((5-methyl- 6-(2,2,3,3-tetrafluoropropoxy)pyridin- 3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 426

(R)-N-(2,3-dihydroxypropyl)-2-((5- methyl-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 427

2-(3-chloro-4-(2,2- difluoroethoxy)benzyl)-N-methyl-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 428

N-methyl-2-(4-(1,1,2,2- tetrafluoroethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 429

2-((5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- methyl-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 430

2-(3-chloro-4-(2,2- difluoroethoxy)benzyl)-N-ethyl-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 431

N-ethyl-2-(4-(1,1,2,2- tetrafluoroethoxy)benzyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 432

2-((5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- ethyl-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 433

N-methyl-2-(1-(4-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide (single enantiomer) 434

N-ethyl-2-(1-(4-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide (single enantiomer) 435

N-(2-acetamidoethyl)-2-(1-(4-methyl- 5-(2,2,2-trifluoroethoxy)pyridin-2- yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide (single enantiomer) 436

N-(2-hydroxyethyl)-2-(1-(4-methyl-5- (2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide (single enantiomer) 437

N-(3-hydroxypropyl)-2-(1-(4-methyl-5- (2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide (single enantiomer) 438

N-((S)-2-hydroxypropyl)-2-(1-(4- methyl-5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide (single enantiomer) 439

N-methyl-2-((5-methyl-6-(3,3,3- trifluoropropyl)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 440

N-ethyl-2-((5-methyl-6-(3,3,3- trifluoropropyl)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 441

N-isopropyl-2-((5-methyl-6-(3,3,3- trifluoropropyl)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 442

N-(2-hydroxyethyl)-2-((5-methyl-6- (3,3,3-trifluoropropyl)pyridin-3-yl) methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 443

N-(3-hydroxypropyl)-2-((5-methyl-6- (3,3,3-trifluoropropyl)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 444

N-methyl-2-((4-methyl-5-(3,3,3- trifluoropropoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 445

N-ethyl-2-((4-methyl-5-(3,3,3- trifluoropropoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 446

N-(2-hydroxyethyl)-2-((4-methyl-5- (3,3,3-trifluoropropoxy)pyridin-2- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 447

N-isopropyl-2-((4-methyl-5-(3,3,3- trifluoropropoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 448

2-((5-chloro-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-N- methyl-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 449

2-((5-chloro-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-N- ethyl-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 450

2-((5-chloro-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-N- isopropyl-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 451

2-((5-chloro-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)- N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 452

2-((5-chloro-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-N- (3-hydroxypropyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 453

(S)-2-((5-chloro-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-N- (2-hydroxypropyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 454

(R)-2-((5-chloro-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-N- (2-hydroxypropyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 455

(S)-2-((5-chloro-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-N- (2,3-dihydroxypropyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 456

(R)-2-((5-chloro-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)- N-(2,3-dihydroxypropyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 457

(S)-2-((5-chloro-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-N- (1-hydroxypropan-2-yl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 458

N-(2-acetamidoethyl)-2-((5-chloro-6- (2,2,3,3-tetrafluoropropoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 459

N-(2-(1-(4-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)isobutyramide (single enantiomer) 460

N-(2-((5-methyl-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)isobutyramide 461

N-(2-((5-methyl-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl) cyclopropanecarboxamide 462

2-hydroxy-2-methyl-N-(2-((5-methyl-6- (2,2,3,3-tetrafluoropropoxy)pyridin-3-yl) methyl)-2H-pyrazolo[4,3-c]pyridin-4- yl)propanamide 463

N-methyl-2-((5-methyl-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 464

N-ethyl-2-((5-methyl-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 465

N-(2-((4-methyl-5-(3,3,3- trifluoropropoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide 466

N-(2-((4-methyl-5-(3,3,3- trifluoropropoxy)pyridin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl) cyclopropanecarboxamide 467

N-(2-((5-methyl-6-(3,3,3- trifluoropropyl)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl) cyclopropanecarboxamide 468

N-(2-((5-methyl-6-(3,3,3- trifluoropropyl)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4- yl)isobutyramide 469

2-((5-chloro-6-(2,2- difluoropropoxy)pyridin-3-yl)methyl)- N-methyl-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 470

2-((5-chloro-6-(2,2- difluoropropoxy)pyridin-3-yl)methyl)- N-ethyl-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 471

2-((5-chloro-6-(2,2- difluoropropoxy)pyridin-3-yl)methyl)- N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 472

2-((5-chloro-6-(2,2- difluoropropoxy)pyridin-3-yl)methyl)-N- (3-hydroxypropyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 473

2-((5-chloro-6-(2,2- difluoropropoxy)pyridin-3-yl)methyl)- N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 474

N-isopropyl-2-((5-methyl-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 475

(S)-N-(1-hydroxypropan-2-yl)-2-((5- methyl-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 476

N-(2-((5-chloro-6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)isobutyramide 477

N-(2-((5-chloro-6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl) cyclopropanecarboxamide 478

N-(2-((5-chloro-6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl)-2- hydroxy-2-methylpropanamide 479

N-(2-((1-methyl-5-(trifluoromethyl)- 1H-benzo[d]imidazol-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl) cyclopropanecarboxamide 480

N-(2-((1-methyl-5-(trifluoromethyl)- 1H-benzo[d]imidazol-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)isobutyramide 481

2-((5-chloro-6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)- N-methyl-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 482

2-((5-chloro-6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)- N-ethyl-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 483

2-((5-chloro-6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)- N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 484

2-((5-chloro-6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)- N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 485

2-((5-chloro-6-(3,3,3- trifluoropropoxy)pyridin-3-yl)methyl)- N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 486

N-(2-(3-chloro-4-(2,2- difluoroethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)isobutyramide 487

N-(2-(3-chloro-4-(2,2- difluoroethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridin-4-yl) cyclopropanecarboxamide 488

N-methyl-2-((1-methyl-5- (trifluoromethyl)-1H-benzo[d]imidazol- 2-yl)methyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 489

N-ethyl-2-((1-methyl-5- (trifluoromethyl)-1H-benzo[d]imidazol- 2-yl)methyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 490

N-isopropyl-2-((1-methyl-5- (trifluoromethyl)-1H-benzo[d]imidazol- 2-yl)methyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 491

N-(2-hydroxyethyl)-2-((1-methyl-5- (trifluoromethyl)-1H-benzo[d]imidazol- 2-yl)methyl)-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 492

N-(3-hydroxypropyl)-2-((1-methyl-5- (trifluoromethyl)-1H-benzo[d]imidazol- 2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 493

N-(2-(4-(2,2-difluoroethoxy)-3- methylbenzyl)-2H-pyrazolo[4,3-c]pyridin-4- yl)isobutyramide 494

N-(2-(4-(2,2-difluoroethoxy)-3- methylbenzyl)-2H-pyrazolo[4,3-c]pyridin-4- yl)cyclopropanecarboxamide 495

N-(2-(4-(2,2-difluoroethoxy)-3- methylbenzyl)-2H-pyrazolo[4,3-c]pyridin-4- yl)-2-hydroxy-2-methylpropanamide 496

2-hydroxy-2-methyl-N-(2-(3-methyl-4- (2,2,2-trifluoroethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)propanamide 497

2-hydroxy-2-methyl-N-(2-(3-methyl-4- (trifluoromethoxy)benzyl)-2H-pyrazolo [4,3-c]pyridin-4-yl)propanamide 498

2-hydroxy-2-methyl-N-(2-(2-(4- (trifluoromethyl)phenoxy)ethyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)propanamide 499

N-(2-((6-(4-chloro-1H-pyrazol-1-yl)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2- methylpropanamide 500

2-(4-(2,2-difluoroethoxy)-3- methylbenzyl)-N-methyl-2H-pyrazolo[4,3-c] pyridine-4-carboxamide 501

2-(4-(2,2-difluoroethoxy)-3- methylbenzyl)-N-ethyl-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 502

N-(2-((5-chloro-6-(2,2- difluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl) cyclopropanecarboxamide 503

N-(2-((5-chloro-6-(2,2- difluoropropoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridin-4-yl) isobutyramide 504

2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- (2-propionamidoethyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 505

N-(2-isobutyramidoethyl)-2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4-carboxamide 506

N-(2-(cyclopropanecarboxamido)ethyl)-2- ((5-methyl-6-(2,2,2-trifluoroethoxy) pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 507

ethyl 2-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamido)ethyl)carbamate 508

N-(2-benzamidoethyl)-2-((5-methyl-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 509

N-(2-(2-hydroxy-2- methylpropanamido)ethyl)-2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 510

2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- (2-(N-methylacetamido)ethyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 511

N-(2-butyramidoethyl)-2-((5-methyl-6- (2,2,2-trifluoroethoxy)pyridin-3-yl) methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 512

N-(2-(cyclobutanecarboxamido)ethyl)- 2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 513

N-(2-(cyclohexanecarboxamido)ethyl)-2- ((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 514

N-(2-(3-ethylureido)ethyl)-2-((5- methyl-6-(2,2,2-trifluoroethoxy) pyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 515

N-(2-acetamidoethyl)-2-((5-chloro-6- (2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 516

N-(2-acetamidoethyl)-2-((6- (cyclopropylmethoxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 517

N-(2-acetamidoethyl)-2-(3-methyl-4- (trifluoromethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 518

N-(2-acetamidoethyl)-2-(3-methyl-4- (2,2,2-trifluoroethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 519

N-(2-acetamidoethyl)-2-(4-(2,2- difluoroethoxy)-3-methylbenzyl)-2H- pyrazolo[4,3-c]pyridine-4-carboxamide 520

N-(2-acetamidoethyl)-2-((5-chloro-6- (3,3,3-trifluoropropoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide 521

N-(2-acetamidoethyl)-2-((1-methyl-5- (trifluoromethoxy)-1H-indol-2- yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4- carboxamide Ex Starting Material Reagent method  2

G  3

G  4

G  5

G  6

G  7

G  8

G  9

G  10

G  11

G  12

G  13

G  14

G  15

G  16

G  17

G  18

G  19

G  20

G  21

G  22

G  23

G  24

G  25

G  26

G  27

G  28

G  29

G  31

NH₃ H  32

H  34

G  35

G  36

G  37

G  38

G  39

G  40

G  41

G  42

G  43

G  44

G  45

G  46

G  47

G  48

G  49

G  50

G  51

G  52

G  53

G  54

G  56

G  57

G  58

G  59

G  60

G  61

G  62

G  63

G  65

G  66

G  67

G  68

NH₃ J  69

H  70

H  71

H  72

H  73

H  74

H  75

H  76

H  77

G  78

G  79

G  80

G  81

G  82

G  83

G  84

G  85

G  86

G  87

G  88

G  89

G  90

G  91

G  92

J  93

H  94

H  95

H  96

H  97

H  98

H  99

H 100

H 101

H 102

G 103

G 104

H 105

H 106

G 107

G 108

G 109

G 110

G 111

G 112

K 113

K 114

G 115

G 116

G 117

G 118

G 119

G 120

G 121

G 122

G 123

L 124

L 125

L 126

L 127

H 128

G 129

G 130

L 131

K 132

L 133

L 134

G 135

H 136

L 137

H 138

H 139

H 140

H 142

H 144

K 145

G 146

G 147

G 148

L 149

L 150

L 151

G 152

G 153

G 154

K 155

K 156

L 157

G 158

G 159

K 160

K 161

G 162

G 163

G 164

G 165

L 166

L 167

L 168

L 169

G 170

G 171

K 172

K 173

L 174

L 175

L 176

L 177

L 178

L 179

L 180

L 181

L 182

L 183

L 184

G 185

G 186

K 187

K 188

L 189

L 190

L 191

G 192

K 193

L 194

L 195

K 196

K 197

L 198

L 199

L 200

L 201

L 202

L 203

K 204

K 205

L 206

L 207

L 208

L 209

L 210

L 211

L 212

L 213

L 214

L 215

K 216

L 217

L 218

L 219

L 220

L 221

L 222

L 223

L 224

L 225

L 226

L 227

G 228

G 229

L 230

L 231

L 232

L 233

L 234

L 235

L 236

L 237

L 238

K 239

K 240

L 241

L 242

L 243

G 244

G 245

L 246

L 247

L 248

L 249

L 250

L 251

L 252

L 253

K 254

K 255

L 256

L 257

L 258

L 259

L 260

L 261

L 262

L 263

L 264

G 265

G 266

G 267

G 268

G 269

L 270

L 271

K 272

K 273

L 274

L 275

K 276

K 277

L 278

L 279

K 280

K 281

L 282

L 283

L 284

G 285

G 286

G 287

G 288

G 290

J 291

J 292

J 293

J 294

J 295

J 296

J 297

J 298

J 299

K 300

K 301

L 302

L 303

K 304

K 305

L 306

L 307

L 308

K 309

K 310

L 311

K 312

K 313

K 314

J 315

J 316

J 317

J 318

K 319

L 320

L 321

L 322

G 323

G 324

G 325

G 326

G 327

G 328

G 329

G 330

K 331

K 332

K 333

L 334

L 335

L 336

L 337

K 338

K 339

L 340

L 341

K 342

K 343

L 344

L 345

K 346

L 347

L 348

L 349

G 350

G 351

K 352

L 353

L 354

K 355

K 356

L 357

L 358

L 359

K 360

K 361

L 362

L 363

L 364

K 365

L 366

L 367

G 368

L 369

L 370

K 371

K 372

L 373

L 374

L 375

L 376

G 377

L 378

K 379

L 380

L 381

L 382

L 383

G 384

G 385

G 386

G 387

G 388

G 389

G 390

G 391

G 392

J 393

J 394

J 395

J 396

J 397

J 398

J 399

G 400

G 401

L 402

L 403

K 404

L 405

L 406

L 407

K 408

K 409

K 410

L 411

L 412

G 413

G 414

G 415

G 416

L 417

L 418

L 419

G 420

G 421

J 422

J 423

J 424

J 425

L 426

L 427

K 428

K 429

K 430

K 431

K 432

K 433

K 434

K 435

L 436

L 437

L 438

L 439

J 440

J 441

J 442

J 443

J 444

K 445

K 446

L 447

L 448

K 449

K 450

L 451

L 452

L 453

L 454

L 455

L 456

L 457

L 458

L 459

G 460

G 461

G 462

G 463

K 464

K 465

G 466

G 467

G 468

G 469

J 470

J 471

J 472

J 473

J 474

L 475

L 476

G 477

G 478

G 479

G 480

G 481

K 482

K 483

L 484

L 485

L 486

G 487

G 488

K 489

K 490

L 491

L 492

L 493

G 494

G 495

G 496

G 497

G 498

499

G 500

K 501

K 502

G 503

G 504

H 505

H 506

H 507

H 508

H 509

H 510

H 511

H 512

H 513

H 514

H 515

L 516

L 517

L 518

L 519

L 520

L 521

L

TABLE 8 Ex Structure Name 522

2-hydroxy-2-methyl-N-(2-((4-methyl- 5-(3,3,3-trifluoropropoxy)pyridin-2- yl)methyl)-2H-pyrazolo[4,3-c]pyridin- 4-yl)propanamide 523

2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- (2-(picolinamido)ethyl)-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 524

2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)-N- (2-(nicotinamido)ethyl)-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 525

N-(2-(isonicotinamido)ethyl)-2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 526

N-(2-(1- hydroxycyclohexanecarboxamido) ethyl)-2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 527

N-(2-acetamidoethyl)-2-(3-chloro-4- (2,2,2-trifluoroethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 528

N-(2-((4-methyl-5-(2,2,3,3- tetrafluoropropoxy)pyridin-2- yl)methyl)-2H-pyrazolo[4,3-c]pyridin- 4-yl)cyclopropanecarboxamide 529

2-hydroxy-2-methyl-N-(2-((4-methyl- 5-(2,2,3,3-tetrafluoropropoxy)pyridin- 2-yl)methyl)-2H-pyrazolo[4,3- c]pyridin-4-yl)propanamide 530

N-(2-((5-chloro-6- (cyclopropylmethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridin- 4-yl)isobutyramide 531

N-(2-((5-chloro-6- (cyclopropylmethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridin- 4-yl)cyclopropanecarboxamide 532

N-(2-((5-chloro-6- (cyclopropylmethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridin- 4-yl)-2-hydroxy-2-methylpropanamide 533

N-methyl-2-((4-methyl-5-(2,2,3,3- tetrafluoropropoxy)pyridin-2- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 534

N-ethyl-2-((4-methyl-5-(2,2,3,3- tetrafluoropropoxy)pyridin-2- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 535

N-isopropyl-2-((4-methyl-5-(2,2,3,3- tetrafluoropropoxy)pyridin-2- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 536

N-(2-acetamidoethyl)-2-((4-methyl-5- (2,2,3,3-tetrafluoropropoxy)pyridin-2- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 537

N-(2-hydroxyethyl)-2-((4-methyl-5- (2,2,3,3-tetrafluoropropoxy)pyridin-2- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 538

N-(3-hydroxypropyl)-2-((4-methyl-5- (2,2,3,3-tetrafluoropropoxy)pyridin-2- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 539

N-methyl-2-(1-(4-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)-2H- pyrazolo[4,3-c]pyridine-4- carboxamide (single enantiomer) 540

N-ethyl-2-(1-(4-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)-2H- pyrazolo[4,3-c]pyridine-4- carboxamide (single enantiomer) 541

N-isopropyl 2-(1-(4-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)-2H- pyrazolo[4,3-c]pyridine-4- carboxamide (single enantiomer) 542

N-(2-acetamidoethyl)-2-((2-methyl-6- (2,2,2-trifluoroethoxy)pyridin-4- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 543

N-(2-acetamidoethyl)-2-(2-(4- (trifluoromethyl)phenoxy)ethyl)-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 544

N-(2-acetamidoethyl)-2-((6-(4-chloro- 1H-pyrazol-1-yl)-5-methylpyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 545

N-(2-acetamidoethyl)-2-((1-(2,2,2- trifluoroethoxy)isoquinolin-4- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 546

N-(2-acetamidoethyl)-2-(4-(1,1,2,2- tetrafluoroethoxy)benzyl)-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 547

N-(2-acetamidoethyl)-2-((2-methoxy- 6-(2,2,2-trifluoroethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 548

N-(2-acetamidoethyl)-2-((6-(2,2- difluoropropoxy)-5-methylpyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 549

N-(2-acetamidoethyl)-2-((6-(2,2,2- trifluoroethoxy)pyridin-2-yl)methyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 550

N-(2-(1-(4-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)cyclopropanecarboxamide (single enantiomer) 551

N-(2-(1-(4-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)isobutyramide (single enantiomer) 552

2-((5-chloro-6- (cyclopropylmethoxy)pyridin-3- yl)methyl)-N-methyl-2H-pyrazolo[4,3- c]pyridine-4-carboxamide 553

2-((5-chloro-6- (cyclopropylmethoxy)pyridin-3- yl)methyl)-N-ethyl-2H-pyrazolo(4,3- c]pyridine-4-carboxamide 554

N-(2-acetamidoethyl)-2-((5-chloro-6- (cyclopropylmethoxy)pyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 555

2-((5-chloro-6- (cyclopropylmethoxy)pyridin-3- yl)methyl)-N-isopropyl-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 556

2-((5-chloro-6- (cyclopropylmethoxy)pyridin-3- yl)methyl)-N-(2-hydroxyethyl)-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 557

2-((5-chloro-6- (cyclopropylmethoxy)pyridin-3- yl)methyl)-N-(3-hydroxypropyl)-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 558

N-(2-((6-((4-fluorobenzyl)oxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)isobutyramide 559

N-(2-((6-((4-fluorobenzyl)oxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)cyclopropanecarboxamide 560

N-(2-((6-((4-fluorobenzyl)oxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)-2- hydroxy-2-methylpropanamide 561

2-((6-((4-fluorobenzyl)oxy)-5- methylpyridin-3-yl)methyl)-N-methyl- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 562

N-ethyl-2-((6-((4-fluorobenzyl)oxy)-5- methylpyridin-3-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 563

N-(2-acetamidoethyl)-2-((6-((4- fluorobenzyl)oxy)-5-methylpyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 564

2-((6-((4-fluorobenzyl)oxy)-5- methylpyridin-3-yl)methyl)-N- isopropyl-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 565

2-((6-((4-fluorobenzyl)oxy)-5- methylpyridin-3-yl)methyl)-N-(2- hydroxyethyl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide 566

2-((6-((4-fluorobenzyl)oxy)-5- methylpyridin-3-yl)methyl)-N-(3- hydroxypropyl)-2H-pyrazolo[4,3- c)pyridine-4-carboxamide 567

N-(2-((6-cyclobutoxy-5-methylpyridin- 3-yl)methyl)-2H-pyrazolo[4,3- c]pyridin-4-yl)-isobutyramide 568

N-(2-((6-cyclobutoxy-5-methylpyridin- 3-yl)methyl)-2H-pyrazolo[4,3- c]pyridin-4-yl) cyclopropanecarboxamide 569

N-(2-((6-cyclobutoxy-5-methylpyridin- 3-yl)methyl)-2H-pyrazolo[4,3- c]pyridin-4-yl)-2-hydroxy-2- methylpropanamide 570

N-(2-((4-methyl-5-(2,2,3,3- tetrafluoropropoxy)pyridin-2- yl)methyl)-2H-pyrazolo[4,3-c]pyridin- 4-yl)isobutyramide 571

2-((6-cyclobutoxy-5-methylpyridin-3- yl)methyl)-N-methyl-2H-pyrazolo[4,3- c]pyridine-4-carboxamide 572

2-((6-cyclobutoxy-5-methylpyridin-3- yl)methyl)-N-ethyl-2H-pyrazolo[4,3- c]pyridine-4-carboxamide 573

N-(2-acetamidoethyl)-2-((6- cyclobutoxy-5-methylpyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 574

2-((6-cyclobutoxy-5-methylpyridin-3- yl)methyl)-N-isopropyl-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 575

2-((6-cyclobutoxy-5-methylpyridin-3- yl)methyl)-N-(2-hydroxyethyl)-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 576

2-((6-cyclobutoxy-5-methylpyridin-3- yl)methyl)-N-(3-hydroxypropyl)-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 577

N-(2-((5-(cyclopropylmethoxy)-4- methylpyridin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)isobutyramide 578

N-(2-((5-(cyclopropylmethoxy)-4- methylpyridin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)cyclopropanecarboxamide 579

N-(2-((5-(cyclopropylmethoxy)-4- methylpyridin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)-2- hydroxy-2-methylpropanamide 580

2-((5-(cyclopropylmethoxy)-4- methylpyridin-2-yl)methyl)-N-methyl- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 581

2-((5-(cyclopropylmethoxy)-4- methylpyridin-2-yl)methyl)-N-ethyl- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 582

N-(2-acetamidoethyl)-2-((5- (cyclopropylmethoxy)-4- methylpyridin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 583

2-((5-(cyclopropylmethoxy)-4- methylpyridin-2-yl)methyl)-N- isopropyl-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 584

2-((5-(cyclopropylmethoxy)-4- methylpyridin-2-yl)methyl)-N-(2- hydroxyethyl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide 585

2-((5-(cyclopropylmethoxy)-4- methylpyridin-2-yl)methyl)-N-(3- hydroxypropyl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide 586

N-methyl-2-((5-methyl-6-(2,2,3,3- tetrafluoropropoxy)pyridazin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 587

N-ethyl-2-((5-methyl-6-(2,2,3,3- tetrafluoropropoxy)pyridazin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 588

N-isopropyl-2-((5-methyl-6-(2,2,3,3- tetrafluoropropoxy)pyridazin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 589

N-(2-hydroxyethyl)-2-((5-methyl-6- (2,2,3,3-tetrafluoropropoxy)pyridazin- 3-yl)methyl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide 590

N-(3-hydroxypropyl)-2-((5-methyl-6- (2,2,3,3-tetrafluoropropoxy)pyridazin- 3-yl)methyl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide 591

N-(2-((5-(2,2-difluoropropoxy)-4- methylpyridin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)isobutyramide 592

N-(2-((5-(2,2-difluoropropoxy)-4- methylpyridin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)cyclopropanecarboxamide 593

2-((5-(2,2-difluoropropoxy)-4- methylpyridin-2-yl)methyl)-N-methyl- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 594

2-((5-(2,2-difluoropropoxy)-4- methylpyridin-2-yl)methyl)-N-ethyl- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 595

N-{2-acetamidoethyl)-2-((5-(2,2- difluoropropoxy)-4-methylpyridin-2- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 596

2-((5-(2,2-difluoropropoxy)-4- methylpyridin-2-yl)methyl)-N- isopropyl-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 597

2-((5-(2,2-difluoropropoxy)-4- methylpyridin-2-yl)methyl)-N-(2- hydroxyethyl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide 598

2-((5-(2,2-difluoropropoxy)-4- methylpyridin-2-yl)methyl)-N-(3- hydroxypropyl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide 599

N-(2-((5-(2,2-difluoropropoxy)-4- methylpyridin-2-yl)methyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)-2- hydroxy-2-methylpropanamide 600

(R)-2-((6-(2,2-difluoropropoxy)-5- methylpyridin-3-yl)methyl)-N-(2- hydroxypropyl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide 601

(S)-2-((6-(2,2-difluoropropoxy)-5- methylpyridin-3-yl)methyl)-N-(2- hydroxypropyl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide 602

(S)-2-((6-(2,2-difluoropropoxy)-5- methylpyridin-3-yl)methyl)-N-(1- hydroxypropan-2-yl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide 603

(S)-2-((6-(2,2-difluoropropoxy)-5- methylpyridin-3-yl)methyl)-N-(2,3- dihydroxypropyl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide 604

(R)-2-((6-(2,2-difluoropropoxy)-5- methylpyridin-3-yl)methyl)-N-(2,3- dihydroxypropyl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide 605

N-(2-cyanoethyl)-2-((6-(2,2- difluoropropoxy)-5-methylpyridin-3- yl)methyl)-2H-pyrazolo[4,3-c]pyridine- 4-carboxamide 606

N-(2-(4-(2,2-difluoropropoxy)-3- methylbenzyl)-2H-pyrazolo[4,3- c]pyridin-4-yl)isobutyramide 607

N-(2-(4-(2,2-difluoropropoxy)-3- methylbenzyl)-2H-pyrazolo[4,3- c]pyridin-4- yl)cyclopropanecarboxamide 608

N-(2-(4-(2,2-difluoropropoxy)-3- methylbenzyl)-2H-pyrazolo[4,3- c]pyridin-4-yl)-2-hydroxy-2- methylpropanamide 609

2-(4-(2,2-difluoropropoxy)-3- methylbenzyl)-N-methyl-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 610

2-(4-(2,2-difluoropropoxy)-3- methylbenzyl)-N-ethyl-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 611

N-(2-acetamidoethyl)-2-(4-(2,2- difluoropropoxy)-3-methylbenzyl)-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 612

2-(4-(2,2-difluoropropoxy)-3- methylbenzyl)-N-isopropyl-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 613

2-(4-(2,2-difluoropropoxy)-3- methylbenzyl)-N-(2-hydroxyethyl)-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 614

2-(4-(2,2-difluoropropoxy)-3- methylbenzyl)-N-(3-hydroxypropyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 615

N-(2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)ethyl)-2H- pyrazolo[4,3-c]pyridin-4-yl)oxazole-5- carboxamide (single enantiomer) 616

2-hydroxy-2-methyl-N-(2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)ethyl)-2H- pyrazolo[4,3-c]pyridin-4- yl)propanamide (single enantiomer) 617

(S)-2-(4-(2,2-difluoroethoxy)-3- methylbenzyl)-N-(2-hydroxypropyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 618

(R)-2-(4-(2,2-difluoroethoxy)-3- methylbenzyl)-N-(2-hydroxypropyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 619

2-(1-(4-(2,2-difluoroethoxy)-3- methylphenyl)ethyl)-N-((R)-2- hydroxypropyl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide (single enantiomer) 620

(R)-2-(4-(2,2-difluoroethoxy)-3,5- dimethylbenzyl)-N-(2-hydroxypropyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 621

(R)-2-(3-(2,2-difluoroethoxy)-4- methylbenzyl)-N-(2-hydroxypropyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 622

2-(1-(4-(2,2-difluoropropoxy)-3- methylphenyl)ethyl)-N-((R)-2- hydroxypropyl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide (single enantiomer) 623

2-(1-(4-(2,2-difluoroethoxy)-3- methylphenyl)ethyl)-N-((R)-2- hydroxypropyl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide (single enantiomer) 624

(S)-2-(4-(2,2-difluoropropoxy)-3- methylbenzyl)-N-(2-hydroxypropyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 625

(R)-2-(4-(2,2-difluoropropoxy)-3- methylbenzyl)-N-(2-hydroxypropyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 626

2-(1-(4-(2,2-difluoroethoxy)-3- methylphenyl)ethyl)-N-((S)-2- hydroxypropyl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide (single enantiomer) 627

(S)-2-(4-(2,2-difluoroethoxy)-3,5- dimethylbenzyl)-N-(2-hydroxypropyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 628

(S)-2-(3-(2,2-difluoroethoxy)-4- methylbenzyl)-N-(2-hydroxypropyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 629

2-(1-(4-(2,2-difluoropropoxy)-3- methylphenyl)ethyl)-N-((S)-2- hydroxypropyl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide (single enantiomer) 630

2-(1-(4-(2,2-difluoroethoxy)-3- methylphenyl)ethyl)-N-((S)-2- hydroxypropyl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide (single enantiomer) 631

(R)-2-(1-(4-(2,2-difluoroethoxy)-3- methylphenyl)ethyl)-N-(2- hydroxyethyl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide 632

2-(4-(2,2-difluoroethoxy)-3,5- dimethylbenzyl)-N-(2-hydroxyethyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 633

2-(3-(2,2-difluoroethoxy)-4- methylbenzyl)-N-(2-hydroxyethyl)-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 634

2-(1-(4-(2,2-difluoropropoxy)-3- methylphenyl)ethyl)-N-(2- hydroxyethyl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide (single enantiomer) 635

2-(1-(4-(2,2-difluoroethoxy)-3- methylphenyl)ethyl)-N-(2- hydroxyethyl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide (single enantiomer) 636

2-(1-(4-(2,2-difluoroethoxy)-3- methylphenyl)ethyl)-N-(3- hydroxypropyl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide (single enantiomer) 637

2-(4-(2,2-difluoroethoxy)-3,5- dirnethylbenzyl)-N-(3-hydroxypropyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 638

2-(3-(2,2-difluoroethoxy)-4- methylbenzyl)-N-(3-hydroxypropyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 639

2-(1-(4-(2,2-difluoropropoxy)-3- methylphenyl)ethyl)-N-(3- hydroxypropyl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide (single enantiomer) 640

2-(1-(4-(2,2-difluoroethoxy)-3- methylphenyl)ethyl)-N-(3- hydroxypropyl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide (single enantiomer) 641

2-(4-(2,2-difluoropropoxy)-3- methylbenzyl)-2H-pyrazolo[4,3- c]pyridine-4-carboxamide 642

2-(4-(difluoromethoxy)-3- methylbenzyl)-N-methyl-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 643

2-(4-(difluoromethoxy)-3- methylbenzyl)-N-ethyl-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 644

N-(2-acetamidoethyl)-2-(4- (difluoromethoxy)-3-methylbenzyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 645

2-(4-(difluoromethoxy)-3- methylbenzyl)-N-(2-hydroxyethyl)-2H- pyrazolo[4,3-c]pyridine-4- carboxamide 646

2-(4-(difluoromethoxy)-3- methylbenzyl)-N-(3-hydroxypropyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 647

(R)-2-(4-(difluoromethoxy)-3- methylbenzyl)-N-(2-hydroxypropyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 648

(S)-2-(4-(difluoromethoxy)-3- methylbenzyl)-N-(2-hydroxypropyl)- 2H-pyrazolo[4,3-c]pyridine-4- carboxamide 649

2-(4-(difluoromethoxy)-3- methylbenzyl)-N-isopropyl-2H- pyrazolo[4,3-c]pyridine-4- carboxamide Ex Starting Material Reagent method 522

G Intermediate-62a 523

H Intermediate-1h 524

H Intermediate-1h 525

H Intermediate-1h 526

H Intermediate-1h 527

L Intermediate-69b 528

G Intermediate-66a 529

G Intermediate-66a 530

G Intermediate-67a 531

G Intermediate-67a 532

G Intermediate-67a 533

K Intermediate-66b 534

K Intermediate-66b 535

L Intermediate-66b 536

L Intermediate-66b 537

L Intermediate-66b 538

L Intermediate-66b 539

K Intermediate-68b 540

K Intermediate-68b 541

L Intermediate-68b 542

L Intermediate-28b 543

L Intermediate-33b 544

L Intermediate-38b 545

L Intermediate-47b 546

L Intermediate-56b 547

L Intermediate-32b 548

L Intermediate-35b 549

L Intermediate-41b 550

G Intermediate-68a 551

G Intermediate-68a 552

K Intermediate-67b 553

K Intermediate-67b 554

L Intermediate-67b 555

L Intermediate-67b 556

L Intermediate-67b 557

L Intermediate-67b 558

G Intermediate-70a 559

G Intermediate-70a 560

G Intermediate-70a 561

K Intermediate-70b 562

K Intermediate-70b 563

L Intermediate-70b 564

L Intermediate-70b 565

L Intermediate-70b 566

L Intermediate-70b 567

G Intermediate-71a 568

G Intermediate-71a 569

G Intermediate-71a 570

G Intermediate-66a 571

K Intermediate-71b 572

K Intermediate-71b 573

L Intermediate-71b 574

L Intermediate-71b 575

L Intermediate-71b 576

L Intermediate-71b 577

G Intermediate-72a 578

G Intermediate-72a 579

G Intermediate-72a 580

K Intermediate-72b 581

K Intermediate-72b 582

L Intermediate-72b 583

L Intermediate-72b 584

L Intermediate-72b 585

L Intermediate-72b 586

K Intermediate-73b 587

K Intermediate-73b 588

L Intermediate-73b 589

L Intermediate-73b 590

L Intermediate-73b 591

G Intermediate-74a 592

G Intermediate-74a 593

K Intermediate-74b 594

K Intermediate-74b 595

L Intermediate-74b 596

L Intermediate-74b 597

L Intermediate-74b 598

L Intermediate-74b 599

G Intermediate-74a 600

L Intermediate-35b 601

L Intermediate-35b 602

L Intermediate-35b 603

L Intermediate-35b 604

L Intermediate-35b 605

L Intermediate-35b 606

G Intermediate-75a 607

G Intermediate-75a 608

G Intermediate-75a 609

K Intermediate-75b 610

K Intermediate-75b 611

L Intermediate-75b 612

L Intermediate-75b 613

L Intermediate-75b 614

L Intermediate-75b 615

G Intermediate-11a 616

G Intermediate-11a 617

L Intermediate-26b 618

L Intermediate-26b 619

L Intermediate-76b 620

L Intermediate-77b 621

L Intermediate-78b 622

L Intermediate-79b 623

L Intermediate-80b 624

L Intermediate-75b 625

L Intermediate-75b 626

L Intermediate-76b 627

L Intermediate-77b 628

L Intermediate-78b 629

L Intermediate-79b 630

L Intermediate-80b 631

L Intermediate-76b 632

L Intermediate-77b 633

L Intermediate-78b 634

L Intermediate-79b 635

L Intermediate-80b 636

L Intermediate-76b 637

L Intermediate-77b 638

L Intermediate-78b 639

L Intermediate-79b 640

L Intermediate-80b 641

NH₃ K Intermediate-75b 642

K Intermediate-81b 643

K Intermediate-81b 644

L Intermediate-81b 645

L Intermediate-81b 646

L Intermediate-81b 647

L Intermediate-81b 648

L Intermediate-81b 649

L Intermediate-81b

TABLE 9 Ex. tR (min) m/z Method 1 1.74 408.1 QC1 2 1.65 424.1 QC1 3 1.54 380.1 QC1 4 1.60 390.2 QC1 5 1.42 362.1 QC1 6 1.51 376.2 QC1 7 1.56 388.1 QC1 8 1.50 406.2 QC1 9 1.61 392.3 QC1 10 1.71 406.4 QC1 11 1.80 420.4 QC1 12 1.67 462.4 QC1 13 1.57 392.1 QC1 14 1.62 394.1 QC1 15 1.73 428.0 QC1 16 1.65 414.0 QC1 17 1.61 470.0 QC1 18 1.44 382.0 QC1 19 1.53 396.1 QC1 20 1.62 410.0 QC1 21 1.55 400.0 QC1 22 1.60 450.1 QC1 23 1.57 433.0 QC1 24 1.67 409.1 QC1 25 1.40 338.1 QC1 26 1.69 408.1 QC1 27 1.69 410.1 QC1 28 1.44 366.1 QC1 29 1.53 380.1 QC1 30 1.76 353.1 QC1 31 1.58 366.1 QC1 32 1.67 380.1 QC1 33 1.88 408.1 QC1 34 1.67 406.1 QC1 35 1.50 392.0 QC1 36 1.54 394.1 QC1 37 1.45 395.1 QC1 38 1.41 393.1 QC1 39 1.47 394.1 QC1 40 1.43 392.1 QC1 41 1.61 408.1 QC1 42 1.56 406.1 QC1 43 1.79 422.0 QC1 44 1.74 420.1 QC1 45 1.61 394.1 QC1 46 1.71 408.1 QC1 47 1.67 464.1 QC1 48 1.57 398.1 QC1 49 1.60 410.0 QC1 50 1.64 412.0 QC1 51 1.83 422.0 QC1 52 1.64 443.0 QC1 53 1.68 406.1 QC1 54 1.55 407.0 QC1 55 1.65 408.1 QC1 56 1.59 418.1 QC1 57 1.56 416.0 QC1 58 1.57 424.0 QC1 59 1.48 432.1 QC1 60 1.54 391.1 QC1 61 1.71 404.1 QC1 62 1.64 393.1 QC1 63 1.59 391.1 QC1 64 1.92 389.2 QC1 65 1.75 444.1 QC1 66 1.71 442.0 QC1 67 1.70 379.1 QC1 68 1.66 380.1 QC1 69 1.77 394.0 QC1 70 1.69 436.0 QC1 71 1.78 406.0 QC1 72 1.92 420.0 QC1 73 1.89 420.0 QC1 74 1.76 464.0 QC1 75 1.73 424.0 QC1 76 1.60 424.0 QC1 77 1.67 408.0 QC1 78 1.77 420.0 QC1 79 1.62 426.0 QC1 80 1.63 402.1 QC1 81 1.59 406.2 QC1 82 1.72 420.2 QC1 83 1.68 418.2 QC1 84 1.72 422.1 QC1 85 1.69 436.1 QC1 86 1.57 418.1 QC1 87 1.53 425.0 QC1 88 1.54 410.0 QC1 89 1.54 410.0 QC1 90 1.71 435.0 QC1 91 1.51 491.1 QC1 92 1.94 422.1 QC1 93 1.87 408.1 QC1 94 1.96 422.0 QC1 95 1.81 438.1 QC1 96 1.68 405.1 QC1 97 1.79 450.0 QC1 98 1.51 437.1 QC1 99 1.66 457.1 QC1 100 1.70 462.1 QC1 101 1.75 443.1 QC1 102 1.69 436.0 QC1 103 1.57 418.1 QC1 104 1.76 438.1 QC1 105 1.84 478.1 QC1 106 1.71 408.1 QC1 107 1.75 420.1 QC1 108 1.79 422.1 QC1 109 1.68 438.1 QC1 110 1.69 408.1 QC1 111 1.77 422.1 QC1 112 1.66 376.1 QC1 113 1.55 362.2 QC1 114 1.64 519.2 QC1 115 1.60 527.2 QC1 116 1.53 477.2 QC1 117 1.53 477.2 QC1 118 1.48 451.1 QC1 119 1.69 424.0 QC1 120 1.56 406.1 QC1 121 1.42 392.1 QC1 122 1.42 392.1 QC1 123 1.76 390.2 QC1 124 1.67 388.0 QC1 125 1.78 402.1 QC1 126 1.98 417.0 QC2 127 2.14 477.2 QC2 128 2.09 455.1 QC2 129 2.04 455.1 QC2 130 1.76 394.1 QC1 131 1.65 380.1 QC1 132 1.67 392.0 QC1 133 1.78 406.0 QC1 134 1.53 457.1 QC1 135 1.55 387.1 QC1 136 1.75 390.1 QC1 137 1.80 433.1 QC1 138 1.63 438.1 QC1 139 1.44 451.1 QC1 140 1.37 409.1 QC1 141 1.51 410.1 QC1 142 1.61 422.1 QC1 143 1.62 380.1 QC1 144 1.72 394.2 QC1 145 1.42 439.1 QC1 146 1.43 443.1 QC1 147 1.43 439.1 QC1 148 1.39 392.2 QC1 149 1.51 423.8 QC1 150 1.48 410.1 QC1 151 1.70 422.2 QC1 152 1.65 420.2 QC1 153 1.60 438.2 QC1 154 1.66 394.2 QC1 155 1.76 408.1 QC1 156 1.86 422.2 QC1 157 1.51 409.2 QC1 158 1.47 407.2 QC1 159 1.46 381.0 QC1 160 1.56 395.1 QC1 161 1.64 477.1 QC1 162 1.54 471.1 QC1 163 1.53 471.1 QC1 164 1.64 475.1 QC1 165 1.67 408.8 QC1 166 1.57 424.1 QC1 167 1.57 424.1 QC1 168 1.44 440.1 QC1 169 1.50 406.1 QC1 170 1.45 424.1 QC1 171 1.50 380.0 QC1 172 1.59 394.1 QC1 173 1.70 408.1 QC1 174 1.38 410.1 QC1 175 1.58 424.1 QC1 176 1.46 423.1 QC1 177 1.56 487.1 QC1 178 1.34 411.1 QC1 179 1.54 424.0 QC1 180 1.43 406.1 QC1 181 1.65 419.1 QC1 182 1.53 401.1 QC1 183 1.48 450.8 QC1 184 1.58 424.2 QC1 185 1.53 422.1 QC1 186 1.53 396.1 QC1 187 1.63 410.1 QC1 188 1.74 424.2 QC1 189 1.40 426.1 QC1 190 1.52 454.1 QC1 191 1.54 408.1 QC1 192 1.69 398.1 QC1 193 1.79 412.1 QC1 194 1.53 430.0 QC1 195 1.56 382.1 QC1 196 1.66 396.1 QC1 197 1.42 412.1 QC1 198 1.77 410.0 QC1 199 1.44 440.1 QC1 200 1.44 395.1 QC1 201 1.52 422.1 QC1 202 1.56 446.1 QC1 203 1.54 380.1 QC1 204 1.65 394.1 QC1 205 1.75 408.1 QC1 206 1.41 410.1 QC1 207 1.51 437.1 QC1 208 1.50 437.1 QC1 209 1.46 437.1 QC1 210 1.75 452.1 QC1 211 1.41 396.0 QC1 212 1.57 438.1 QC1 213 1.44 410.1 QC1 214 1.54 409.1 QC1 215 1.65 412.1 QC1 216 1.43 428.0 QC1 217 1.51 465.2 QC1 218 1.58 501.1 QC1 219 1.75 426.1 QC1 220 1.44 391.1 QC1 221 1.47 405.2 QC1 222 1.51 442.1 QC1 223 1.54 456.1 QC1 224 1.56 444.1 QC1 225 1.45 426.0 QC1 226 1.47 409.1 QC1 227 1.72 408.2 QC1 228 1.67 406.1 QC1 229 1.57 423.1 QC1 230 1.54 438.1 QC1 231 1.37 425.1 QC1 232 1.40 424.1 QC1 233 1.43 440.1 QC1 234 1.48 428.1 QC1 235 1.56 436.1 QC1 236 1.59 460.1 QC1 237 1.44 424.1 QC1 238 1.66 380.1 QC1 239 1.77 394.1 QC1 240 1.87 408.2 QC1 241 1.52 410.1 QC1 242 1.55 424.1 QC1 243 1.57 408.2 QC1 244 1.53 406.2 QC1 245 1.57 438.1 QC1 246 1.57 437.7 QC1 247 1.44 454.2 QC1 248 1.44 454.2 QC1 249 1.32 440.1 QC1 250 1.85 430.1 QC1 251 1.51 432.1 QC1 252 1.54 446.2 QC1 253 1.65 402.1 QC1 254 1.75 416.2 QC1 255 1.43 424.1 QC1 256 1.43 424.0 QC1 257 1.58 438.1 QC1 258 1.44 424.2 QC1 259 1.50 419.1 QC1 260 1.65 433.1 QC1 261 1.48 465.1 QC1 262 1.45 437.1 QC1 263 1.71 438.2 QC1 264 1.65 452.1 QC1 265 1.61 450.1 QC1 266 1.55 468.0 QC1 267 1.72 424.1 QC1 268 1.68 422.1 QC1 269 1.47 454.1 QC1 270 1.50 468.1 QC1 271 1.61 424.1 QC1 272 1.71 438.1 QC1 273 1.53 426.1 QC1 274 1.56 440.0 QC1 275 1.67 396.1 QC1 276 1.77 409.7 QC1 277 1.81 452.1 QC1 278 1.87 424.1 QC1 279 1.63 364.8 QC1 280 1.73 379.1 QC1 281 1.83 393.1 QC1 282 1.48 395.1 QC1 283 1.51 409.1 QC1 284 1.60 409.1 QC1 285 1.56 407.0 QC1 286 1.65 404.1 QC1 287 1.60 402.1 QC1 288 1.55 420.1 QC1 289 1.66 400.0 QC1 290 1.77 413.9 QC1 291 1.88 428.0 QC1 292 1.51 430.0 QC1 293 1.54 443.7 QC1 294 1.74 406.1 QC1 295 1.84 420.1 QC1 296 1.94 434.1 QC1 297 1.60 436.1 QC1 298 1.63 450.0 QC1 299 1.60 376.0 QC1 300 1.71 390.1 QC1 301 1.46 406.1 QC1 302 1.49 420.1 QC1 303 1.54 381.1 QC1 304 1.65 395.1 QC1 305 1.44 425.0 QC1 306 1.81 404.1 QC1 307 1.76 409.1 QC1 308 1.57 382.1 QC1 309 1.69 396.1 QC1 310 1.59 424.1 QC1 311 1.62 438.1 QC1 312 1.74 394.1 QC1 313 1.84 408.1 QC1 314 1.59 424.0 QC1 315 1.62 438.0 QC1 316 1.74 394.0 QC1 317 1.84 408.1 QC1 318 1.61 348.2 QC1 319 1.55 424.0 QC1 320 1.80 410.1 QC1 321 1.43 412.1 QC1 322 1.78 422.1 QC1 323 1.68 438.0 QC1 324 1.62 374.1 QC1 325 1.63 394.1 QC1 326 1.59 392.0 QC1 327 1.72 380.1 QC1 328 1.67 378.1 QC1 329 1.61 396.1 QC1 330 1.74 394.1 QC1 331 1.84 408.1 QC1 332 1.54 393.1 QC1 333 1.65 407.1 QC1 334 1.30 409.1 QC1 335 1.33 422.9 QC1 336 1.89 380.0 QC1 337 1.55 366.1 QC1 338 1.66 380.1 QC1 339 1.41 396.1 QC1 340 1.44 410.1 QC1 341 1.67 352.2 QC1 342 1.78 366.1 QC1 343 1.51 382.2 QC1 344 1.54 395.9 QC1 345 1.83 379.1 QC1 346 1.93 393.0 QC1 347 1.58 395.0 QC1 348 1.61 409.1 QC1 349 1.65 380.1 QC1 350 1.79 468.1 QC1 351 1.73 365.1 QC1 352 1.46 426.1 QC1 353 1.76 394.1 QC1 354 1.66 392.1 QC1 355 1.77 406.1 QC1 356 1.58 424.1 QC1 357 1.61 438.1 QC1 358 1.56 500.1 QC1 359 1.76 416.0 QC1 360 1.86 430.0 QC1 361 1.96 444.1 QC1 362 1.61 446.0 QC1 363 1.64 460.1 QC1 364 1.69 393.1 QC1 365 1.48 423.0 QC1 366 1.79 407.1 QC1 367 1.47 422.0 QC1 368 1.27 392.1 QC1 369 1.30 405.8 QC1 370 1.77 404.0 QC1 371 1.87 418.1 QC1 372 1.96 432.1 QC1 373 1.63 434.1 QC1 374 1.43 411.0 QC1 375 1.46 425.0 QC1 376 1.48 422.1 QC1 377 1.57 486.1 QC1 378 1.53 408.1 QC1 379 1.64 422.1 QC1 380 1.31 424.1 QC1 381 1.34 438.1 QC1 382 1.66 448.1 QC1 383 1.43 420.1 QC1 384 1.43 390.1 QC1 385 1.39 388.1 QC1 386 1.34 406.1 QC1 387 1.64 377.1 QC1 388 1.68 379.1 QC1 389 1.58 395.0 QC1 390 1.60 410.1 QC1 391 1.64 412.0 QC1 392 1.63 351.1 QC1 393 1.84 379.1 QC1 394 1.48 381.1 QC1 395 1.52 395.1 QC1 396 1.69 398.1 QC1 397 1.80 412.1 QC1 398 1.48 428.1 QC1 399 1.59 444.1 QC1 400 1.55 442.1 QC1 401 1.46 413.1 QC1 402 1.49 427.1 QC1 403 1.63 430.1 QC1 404 1.73 444.1 QC1 405 1.45 460.1 QC1 406 1.59 390.2 QC1 407 1.38 362.1 QC1 408 1.49 376.1 QC1 409 1.52 412.0 QC1 410 1.31 428.1 QC1 411 1.34 442.0 QC1 412 1.70 460.0 QC1 413 1.66 458.0 QC1 414 1.61 476.0 QC1 415 1.48 426.1 QC1 416 1.48 483.1 QC1 417 2.08 456.1 QC2 418 1.91 472.1 QC2 419 1.59 361.1 QC1 420 1.64 363.2 QC1 421 1.59 335.1 QC1 422 1.69 349.1 QC1 423 1.80 363.1 QC1 424 1.47 379.1 QC1 425 1.56 456.1 QC1 426 1.44 472.1 QC1 427 1.56 381.1 QC1 428 1.59 383.1 QC1 429 1.67 400.0 QC1 430 1.66 395.1 QC1 431 1.69 396.9 QC1 432 1.76 413.9 QC1 433 1.58 394.1 QC1 434 1.68 408.1 QC1 435 1.43 465.1 QC1 436 1.45 424.0 QC1 437 1.48 438.1 QC1 438 1.51 438.1 QC1 439 1.52 378.1 QC1 440 1.63 392.2 QC1 441 1.74 406.1 QC1 442 1.39 408.1 QC1 443 1.42 422.1 QC1 444 1.52 394.2 QC1 445 1.62 408.1 QC1 446 1.40 424.1 QC1 447 1.72 422.1 QC1 448 1.67 431.8 QC1 449 1.76 446.0 QC1 450 1.86 460.1 QC1 451 1.53 462.0 QC1 452 1.56 476.0 QC1 453 1.59 476.0 QC1 454 1.59 476.0 QC1 455 1.47 492.0 QC1 456 1.47 491.9 QC1 457 1.60 475.9 QC1 458 1.51 503.1 QC1 459 1.62 422.1 QC1 460 1.68 440.1 QC1 461 1.64 438.1 QC1 462 1.59 456.0 QC1 463 1.65 412.1 QC1 464 1.74 426.1 QC1 465 1.57 422.1 QC1 466 1.53 420.1 QC1 467 1.53 404.1 QC1 468 1.57 406.1 QC1 469 2.14 396.1 QC2 470 2.31 410.2 QC2 471 2.48 424.2 QC2 472 2.03 440.1 QC2 473 1.98 426.2 QC2 474 2.49 440.3 QC2 475 2.11 456.2 QC2 476 2.31 442.2 QC2 477 2.23 440.2 QC2 478 2.16 458.2 QC2 479 1.94 415.2 QC2 480 2.01 417.2 QC2 481 2.21 414.0 QC2 482 2.38 428.2 QC2 483 2.53 442.2 QC2 484 2.04 444.1 QC2 485 2.09 458.1 QC2 486 2.13 409.2 QC2 487 2.06 407.2 QC2 488 1.93 389.2 QC2 489 2.08 403.1 QC2 490 2.23 417.2 QC2 491 1.78 419.2 QC2 492 1.83 433.2 QC2 493 2.14 389.3 QC2 494 2.08 387.3 QC2 495 2.01 405.3 QC2 496 2.16 423.2 QC2 497 2.21 409.2 QC2 498 2.08 409.2 QC2 499 1.93 426.2 QC2 500 2.04 361.2 QC2 501 2.19 375.2 QC2 502 2.14 422.2 QC2 503 2.23 424.2 QC2 504 1.54 465.1 QC1 505 1.60 479.1 QC1 506 1.58 477.1 QC1 507 1.67 481.1 QC1 508 1.69 513.1 QC1 509 1.50 495.1 QC1 510 1.54 465.0 QC1 511 1.60 479.1 QC1 512 1.63 491.1 QC1 513 1.74 519.2 QC1 514 1.52 480.1 QC1 515 1.50 471.0 QC1 516 1.48 423.2 QC1 517 1.54 436.1 QC1 518 1.51 450.1 QC1 519 1.42 432.1 QC1 520 1.51 485.0 QC1 521 1.60 475.1 QC1 522 1.93 438.2 QC2 523 1.66 514.0 QC1 524 1.52 514.0 QC1 525 1.53 514.0 QC1 526 1.63 535.0 QC1 527 1.49 469.9 QC1 528 1.51 438.0 QC1 529 1.46 456.0 QC1 530 1.75 400.0 QC1 531 1.70 398.0 QC1 532 1.64 416.0 QC1 533 1.51 412.0 QC1 534 1.60 426.0 QC1 535 1.69 440.0 QC1 536 1.38 483.0 QC1 537 1.39 442.0 QC1 538 1.42 456.0 QC1 539 1.58 394.0 QC1 540 1.68 408.0 QC1 541 1.79 422.0 QC1 542 1.49 451.0 QC1 543 1.46 435.9 QC1 544 1.40 452.9 QC1 545 1.58 487.0 QC1 546 1.44 454.0 QC1 547 1.50 467.0 QC1 548 1.44 447.0 QC1 549 1.38 437.0 QC1 550 1.58 420.0 QC1 551 1.62 422.0 QC1 552 1.71 372.0 QC1 553 1.81 386.0 QC1 554 1.52 443.0 QC1 555 1.92 400.0 QC1 556 1.55 402.0 QC1 557 1.58 416.0 QC1 558 1.81 434.1 QC1 559 1.76 432.1 QC1 560 1.71 450.1 QC1 561 1.77 406.1 QC1 562 1.86 420.1 QC1 563 1.59 477.1 QC1 564 1.96 434.1 QC1 565 1.62 436.1 QC1 566 1.65 450.1 QC1 567 1.78 380.2 QC1 568 1.73 378.2 QC1 569 1.66 396.2 QC1 570 1.55 440.0 QC1 571 1.73 352.0 QC1 572 1.84 366.1 QC1 573 1.52 423.0 QC1 574 1.96 380.1 QC1 575 1.56 382.0 QC1 576 1.59 396.0 QC1 577 1.59 380.1 QC1 578 1.54 378.0 QC1 579 1.48 396.0 QC1 580 1.53 352.0 QC1 581 1.64 366.1 QC1 582 1.38 423.0 QC1 583 1.75 380.1 QC1 584 1.40 382.0 QC1 585 1.43 396.0 QC1 586 1.47 413.2 QC1 587 1.56 427.2 QC1 588 1.66 441.2 QC1 589 1.36 443.2 QC1 590 1.38 457.2 QC1 591 1.52 404.3 QC1 592 1.48 402.3 QC1 593 1.47 376.3 QC1 594 1.57 390.3 QC1 595 1.34 447.3 QC1 596 1.67 404.4 QC1 597 1.36 406.3 QC1 598 1.38 420.3 QC1 599 1.84 418.2 QC2 600 1.51 420.2 QC1 601 1.51 420.2 QC1 602 1.53 420.2 QC1 603 1.39 436.2 QC1 604 1.39 436.2 QC1 605 1.59 415.2 QC1 606 1.70 403.3 QC1 607 1.65 401.2 QC1 608 1.60 419.3 QC1 609 1.65 375.2 QC1 610 1.75 389.3 QC1 611 1.49 446.2 QC1 612 1.84 403.2 QC1 613 1.51 405.2 QC1 614 1.54 419.2 QC1 615 1.62 447.1 QC1 616 1.67 438.2 QC1 617 1.48 403.3 QC1 618 1.48 403.3 QC1 619 1.55 417.4 QC1 620 1.52 417.4 QC1 621 1.51 405.3 QC1 622 1.64 431.4 QC1 623 1.55 417.3 QC1 624 1.56 417.4 QC1 625 1.56 417.4 QC1 626 1.55 417.4 QC1 627 1.52 417.4 QC1 628 1.51 405.3 QC1 629 1.64 431.1 QC1 630 1.56 417.1 QC1 631 1.50 403.1 QC1 632 1.47 403.1 QC1 633 1.46 389.1 QC1 634 1.58 417.1 QC1 635 1.50 403.1 QC1 636 1.53 417.1 QC1 637 1.50 417.1 QC1 638 1.49 403.1 QC1 639 1.61 431.1 QC1 640 1.53 417.2 QC1 641 2.03 359.2 QC2 642 1.56 345.2 QC1 643 1.66 359.2 QC1 644 1.40 416.3 QC1 645 1.42 375.3 QC1 646 1.45 389.3 QC1 647 1.48 389.3 QC1 648 1.48 389.3 QC1 649 1.76 373.3 QC1

Ex 1H-NMR data Salt Table 10-1 1 (300 MHz, CDCl₃) δ 8.83 (1H, s), 8.39 (1H, br), 8.03 (1H, d, J = 2.2 Hz), 7.85 free (1H, br), 7.45 (1H, s), 7.30 (1H, d, J = 6.6 Hz), 5.48 (2H, s), 4.75 (2H, q, J = 8.6 Hz), 2.65 (1H, septet, 6.6 Hz), 2.19 (3H, s), 1.30 (6H, d, J = 6.6 Hz) 2 (300 MHz, DMSO-d₆) δ 9.68 (1H, s), 9.00 (1H, s), 8.16 (1H, s), 7.86 (1H, d, J = free 5.9 Hz), 7.69 (1H, s), 7.29 (1H, d, J = 5.9 Hz), 6.14 (1H, s), 5.66 (2H, s), 4.99 (2H, q, J = 8.8 Hz), 2.15 (3H, s), 1.43 (6H, s). 69 (300 MHz, CDCl₃) δ 8.84 (1H, s), 8.25 (1H, dd, J = 5.8 and 2.2 Hz), 8.06 (2H, s), free 7.68 (1H, d, J = 5.8 Hz), 7.45 (1H, s), 5.55 (2H, s), 4.81-4.71 (2H, m), 3.58-3.48 (2H, m), 2.20 (3H, s), 1.33-1.27 (3H, m) 141 (300 MHz, DMSO-d₆) δ 9.17 (1H, s), 8.76 (1H, t, J = 5.9 Hz), 8.25 (1H, d, J = 5.9 free Hz), 8.19 (1H, s), 7.76-7.73 (2H, m), 5.73 (2H, s), 4.99 (2H, q, J = 8.8 Hz), 4.83 (1H, t, J = 5.1 Hz), 3.60-3.52 (2H, m), 3.45-3.38 (2H, m), 2.15 (3H, s) 149 (300 MHz, CDCl₃) δ 8.79 (1H, s), 8.45 (1H,br), 8.24 (1H, d, J = 6.6 Hz), 8.06 free (1H, d, J = 2.2 Hz), 7.69 (1H, d, J = 6.6 Hz), 7.41 (1H, s), 5.54 (2H, s), 4.56 (2H, t, J = 6.2 Hz), 3.90-3.84 (2H, m), 3.70-3.64 (2H, m), 2.75 (1H, t, J = 5.1 Hz), 2.69-2.54 (2H, m), 2.15 (3H, s) 158 (300 MHz, CDCl₃) δ 10.03 (1H, br s), 8.87 (1H, s), 7.90-7.82 (1H, m), 7.29-7.24 free (2H, m), 5.79 (2H, s), 4.93 (2H, q, J = 8.1 Hz), 2.22 (3H, s), 1.81-1.70 (1H, m), 1.18-1.11 (2H, m), 0.97-0.90 (2H, m) 166 (300 MHz, CDCl₃) δ 8.80 (1H, s), 8.47-8.41 (1H, m), 8.23 (1H, d, J = 5.9 Hz), free 8.06 (1H, d, J = 1.5 Hz), 7.68 (1H, d, J = 5.9 Hz), 7.46 (1H, s), 5.55 (2H, s), 4.76 (2H, q, J = 8.8 Hz), 4.12-4.04 (1H, m), 3.68-3.60 (1H, m), 3.45-3.35 (1H, m), 2.91 (1H, d, J = 4.4 Hz), 2.20 (3H, s), 1.28 (3H, d, J = 5.9 Hz) 172 (300 MHz, CDCl₃) δ 8.95 (1H, s), 8.23 (1H, d, J = 6.6 Hz), 8.12 (1H, s), 8.07 free (1H, br), 7.68 (1H, d, J = 6.6 Hz), 7.08 (1H, s), 5.69 (2H, s), 4.43 (2H, q, J = 8.0 Hz), 3.54 (2H, quintet, J = 6.6 Hz), 2.23 (3H, s), 1.30 (3H, t, J = 7.3 Hz) 174 (300 MHz, CDCl₃) δ 8.93 (1H, s), 8.45 (1H, br), 8.24 (1H, d, J = 6.6 Hz), 8.12 free (1H, s), 7.70 (1H, d, J = 6.6 Hz), 7.09 (1H, s), 4.43 (2H, q, J = 8.0 Hz), 3.92- 3.84 (2H, m), 3.72-3.65 (2H, m), 2.77 (1H, t, J = 5.1 Hz), 2.24 (3H, s) 179 (270 MHz, DMSO-d₆) δ 9.17 (1H, s), 8.90 (1H, t, J = 5.3 Hz), 8.25-8.20 (2H, m), free 7.75-7.73 (2H, m), 5.73 (2H, s), 5.00 (2H, q, J = 9.2 Hz), 4.55 (1H, t, J = 5.3 Hz), 3.52-3.34 (4H, m), 2.15 (3H, s), 1.71 (2H, quintet, J = 6.6 Hz) 183 (300 MHz, CDCl₃) δ 8.80 (1H, s), 8.40 (1H, br), 8.27 (1H, d, J = 5.8 Hz), 8.07 free (1H, s), 7.70 (1H, d, J = 5.8 Hz), 7.47 (1H, s), 6.20 (1H, br), 5.57 (2H, s), 4.76 (2H, q, J = 8.8 Hz), 3.68-3.61 (2H, m), 3.55-3.49 (2H, m), 2.20 (3H, s), 1.99 (3H, s) 199 (300 MHz, CDCl₃) δ 8.80 (1H, s), 8.47 (1H, br), 8.25 (1H, d, J = 6.6 Hz), 8.07 free (1H, d, J = 2.2 Hz), 7.71 (1H, d, J = 6.6 Hz), 7.46 (1H, d, J = 2.2 Hz), 5.56 (2H, s), 4.76 (2H, q, J = 8.8 Hz), 3.96-3.86 (1H, m), 3.75-3.58 (4H, m), 3.09- 3.01 (2H, m), 2.21 (3H, s) Table 10-2 220 (300 MHz, CDCl₃) δ 8.76 (1H, s), 8.52-8.40 (1H, m), 8.24 (1H, d, J = 6.2 Hz), free 7.70 (1H, d, J = 6.2 Hz), 7.27-7.15 (2H, m), 6.78 (1H, d, J = 8.1 Hz), 6.10 (1H, tt, J = 55.0, 4.0 Hz), 5.55 (2H, s), 4.18 (2H, td, J = 13.0, 4.0 Hz), 3.91-3.80 (2H, m), 3.72-3.61 (2H, m), 2.22 (3H, s) (a signal due to OH is not observed) 222 (300 MHz, CDCl₃) δ 8.81 (1H, s), 8.48-8.42 (1H, m), 8.25 (1H, d, J = 5.9 Hz), free 8.07 (1H, d, J = 2.2 Hz), 7.69 (1H, d, J = 5.9 Hz), 7.45 (1H, s), 5.99 (1H, tt, J = 52.8 and 4.4 Hz), 5.56 (2H, s), 4.74 (2H, t, J = 12.5 Hz), 3.91-3.85 (2H, m), 3.70-3.64 (2H, m), 2.74 (1H, t, J = 5.9 Hz), 2.18 (3H, s) 223 (300 MHz, CDCl₃) δ 8.83 (1H, s), 8.36-8.28 (1H, m), 8.25 (1H, d, J = 5.9 Hz), free 8.07 (1H, s), 7.70 (1H, d, J = 5.9 Hz), 7.46 (1H, s), 5.98 (1H, tt, J = 53.6 and 4.4 Hz), 5.56 (2H, s), 4.74 (2H, t, J = 12.5 Hz), 3.70-63 (4H, m), 3.30 (1H, br s), 2.19 (3H, s), 1.87-1.79 (2H, m) 288 (300 MHz, DMSO-d₆) δ 9.67 (1H, s), 8.98 (1H, s), 8.13 (1H, s), 7.85 (1H, d, J = free 5.9 Hz), 7.63 (1H, s), 7.28 (1H, d, J = 5.9 Hz), 6.14 (1H, s), 5.63 (2H, s), 4.54 (2H, t, J = 13.2 Hz), 2.12 (3H, s), 1.71 (3H, t, J = 19.1 Hz), 1.41 (6H, s) 301 (300 MHz, CDCl₃) δ 8.79 (1H, s), 8.45 (1H, br s), 8.24 (1H, d, J = 6.6 Hz), 8.07 free (1H, s), 7.69 (1H, d, J = 6.6 Hz), 7.43 (1H, s), 5.55 (2H, s), 4.50 (2H, t, J = 11.7 Hz), 3.90-3.85 (2H, m), 3.70-3.64 (2H, m), 2.83 (1H, t, J = 5.5 Hz), 2.19 (3H, s), 1.74 (3H, t, J = 19.1 Hz) 343 (300 MHz, CDCl₃) δ 8.75 (1H, s), 8.51-8.39 (1H, m), 8.23-8.19 (1H, m), 8.05 free (1H, d, J = 2.2 Hz), 7.67 (1H, d, J = 6.6 Hz), 7.38 (1H, s), 5.22 (2H, s), 4.16-4.14 (2H, m), 3.89-3.85 (2H, m), 3.69-3.63 (2H, m), 3.02 (1H, br s), 2.17 (3H, s), 1.35-1.21 (1H, m), 0.61-0.56 (2H, m), 0.37-0.32 (2H, m) 462 (300 MHz, DMSO-d₆) δ 9.67 (1H, s), 9.00 (1H, s), 8.15 (1H, s), 7.85 (1H, d, J = free 5.9 Hz), 7.66 (1H, s), 7.28 (1H, d, J = 5.9 Hz), 6.66 (1H, tt, J = 52.1, 5.1 Hz), 6.14 (1H, s), 5.64 (2H, s), 4.83 (2H, t, J = 13.9 Hz), 2.13 (3H, s), 1.41 (6H, s) 518 (300 MHz, DMSO-d₆) δ 9.07 (1H, s), 8.93 (1H, t, J = 5.9 Hz), 8.24 (1H, d, J = 5.9 free Hz), 8.02-7.94 (1H, m), 7.73 (1H, d, J = 5.9 Hz), 7.28 (2H, s), 7.03 (1H, d, J = 8.8 Hz), 5.65 (2H, s), 4.73 (2H, q, J = 8.1 Hz), 3.41-3.19 (4H, m), 2.13 (3H, s), 1.78 (3H, s)

Pharmacological Assays

In vitro human voltage gated sodium channels activity

The inhibitory activities of compounds against voltage gated sodium channels are determined by methodology well known in the art.

The ability of the pyrazolopyridine derivatives of the formula (I) to inhibit the Na_(v1.3), Na_(v1.7) and Na_(v1.5) channels is measured by Fluorescence Resonance Energy Transfer (FRET) assay and electrophysiology assay described below.

FRET Assay

This screen is used to determine the effects of compounds on human Na_(v1.3), human Na_(v1.7), and human Na_(v1.5) channels, utilising electrical field stimulation (EFS) system in 96-well plate format on FDSS (Hamamatsu Photonics) platform. The change of membrane potential is monitored with FRET dye pair, oxonol (DiSBAC2(3)) and coumarin (CC2-DMPE).

Cell Maintenance:

Each HEK293 cells expressing human Na_(v1.3) channels and HEK293 cells expressing human Na_(v1.5) channels are grown in T225 flasks, in a 5% CO₂ humidified incubator to about 80% confluence. Media composition consists of Dulbecco's Modified Eagle Medium (high glucose), 10% FCS, 100 units/mL penicillin, 100 microgram/mL streptomycin and 500 microgram/mL Geneticine.

CHO cells expressing human Na_(v1.7) channels are grown in T225 flasks, in a 5% CO₂ humidified incubator to about 80% confluence. Media composition consists of HAM/F12 with Glutamax I, 10% FCS, 100 units/mL penicillin and 100 microgram/mL hygromycin.

Protocol:

-   -   Seed each cell lines (1×10⁵ cell/swell) into poly-D-lysine         coated 96-well plates prior to experimentation.     -   Incubate at 37° C. in 5% CO₂ for 24 hours.     -   Wash each well with assay buffer (140 mM NaCl, 4.5 mM KCl, 10 mM         D-Glucose, 2 mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES, pH 7.4 adjusted         with NaOH) twice.     -   Add 1st loading solution containing 10 microM CC2-DMPE and 0.06%         Pluronic F-127 in assay buffer.     -   Incubate the plate at room temperature in dark for 1 hour.     -   Remove 1st loading solution and added 2nd loading solution         containing 15 microM DiSBAC2(3), 0.555 mM VABSC-1 and 0.004%         Pluronic F-127 in assay buffer.     -   Place the plate under the dark at room temperature for 25         minutes.     -   Add compound solutions into the assay plate.     -   Set the assay plate in FDSS and placed an EFS device on the         plate.     -   Measure EFS-induced fluorescent response by FDSS.

The data are analyzed and reported as normalized ratios of intensities measured at 440 nm. The process of calculating these ratios is performed as follows:

$\begin{matrix} {{{F\; I\; R} = {{{Fluorescence}\mspace{14mu}{Integration}\mspace{14mu}{Ratio}} = {{the}\mspace{14mu}{integral}\mspace{14mu}{of}\mspace{14mu}{the}\mspace{14mu}{ratio}\mspace{14mu}{normalized}\mspace{14mu}{by}\mspace{14mu}{baseline}\mspace{14mu}\left( {{before}\mspace{14mu}{EFS}} \right)}}}{{\%\mspace{14mu}{inhibition}} = {\left\{ {1 - \frac{\left( {{F\; I\; R\mspace{14mu}{of}\mspace{14mu}{each}\mspace{14mu}{well}} - {{median}\mspace{14mu} F\; I\; R\mspace{14mu}{in}\mspace{14mu} 100\%\mspace{14mu}{{Inh}.}}} \right)}{\begin{pmatrix} {{median}\mspace{14mu} F\; I\; R\mspace{14mu}{in}\mspace{20mu} 0\%\mspace{14mu}{{Inh}. -}} \\ {{median}\mspace{14mu} F\; I\; R\mspace{14mu}{in}\mspace{14mu} 100\%\mspace{14mu}{{Inh}.}} \end{pmatrix}}} \right\} \times 100}}} & \left\lbrack {{Math}.\mspace{11mu} 1} \right\rbrack \end{matrix}$

This analysis is performed using a computerized specific program designed for FDSS generated data. Fluorescence ratio values are plotted using XLfit to determine an IC₅₀ value for each compound.

All tested compounds show less than about 3 microM of IC₅₀ against Na_(v1.3) and/or Na_(v1.7) in the above assays. Preferable compounds show less than about 1 microM of IC₅₀ against Na_(v1.7) and/or Na_(v1.3) in the above assays.

Compounds with IC₅₀ against Na_(v1.7)<1 microM and/or Na_(v1.3)<1 microM are: Examples 1, 2, 3, 4, 6, 7, 9, 10, 11, 14, 15, 16, 18, 19, 20, 21, 22, 25, 27, 32, 33, 34, 38, 41, 42, 43, 44, 45, 46, 47, 51, 52, 61, 65, 69, 71, 75, 80, 82, 85, 88, 89, 92, 93, 96, 98, 103, 104, 106, 107, 108, 109, 112, 113, 119, 120, 125, 126, 128, 129, 134, 139, 141, 145, 147, 148, 149, 151, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 187, 190, 191, 194, 195, 196, 197, 199, 201, 202, 203, 204, 207, 209, 212, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 227, 228, 229, 230, 231, 232, 238, 239, 240, 241, 242, 245, 246, 247, 248, 251, 252, 254, 255, 256, 257, 258, 259, 260, 261, 262, 264, 265, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 304, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 320, 321, 322, 326, 327, 328, 329, 330, 331, 332, 333, 335, 336, 337, 338, 341, 342, 343, 344, 345, 347, 348, 349, 350, 351, 352, 355, 356, 357, 358, 359, 360, 362, 363, 364, 367, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 380, 382, 383, 384, 385, 386, 387, 391, 392, 394, 395, 399, 400, 401, 402, 403, 406, 407, 408, 409, 412, 413, 414, 415, 416, 417, 418, 420, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 489, 492, 493, 494, 495, 496, 497, 500, 501, 502, 503, 504, 506, 507, 508, 512, 513, 515, 516, 517, 518, 519, 521, 522, 523, 524, 525, 527, 528, 529, 530, 531, 532, 533, 534, 535, 537, 538, 540, 545, 548, 549, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 596, 597, 598, 599, 600, 602, 603, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 616, 617, 618, 619, 620, 622, 624, 625, 626, 627, 629, 631, 632, 633, 634, 636, 637, 639, 640, 641, 642, 643, 645, 646, and 649. Regarding all tested compounds, the ratio of activities against Na_(v1.5) vs. Na_(v1.3) or Na_(v1.7) is more than three times. For example, the activities of Example 2 against Na_(v1.5) and Na_(v1.7) are more than 30 microM and 0.38 microM, respectively.

Electrophysiology Assay for Nays

Whole cell patch clamp recording is used to assess the efficacy or selectivity of Na channel blocker on human Na_(v1.3) (hSCN3A) expressing HEK293 cells or human Na_(v1.7) (hSCN9A) expressing CHO cells. Human Na_(v1.3) expressing HEK293 cells are grown in growth media which contain: DMEM, 10% heat-inactivated FBS (Hyclone Laboratories Inc), 100 microgram/mL penicillin/100U/mL streptomycin, 150 microgram/mL Zeocin, and 3 microgram/mL Geneticin. Human Na_(v1.7) expressing CHO cells are grown in growth media which contain: HAMF-12, 9% heat-inactivated FBS (Hyclone Laboratories Inc), and 100 microgram/mL penicillin/100 U/mL streptomycin, and 100 microgram/mL hygromycin.

Na channel expressing cells are dissociated by 0.05% Trypsine-EDTA, and then seeded on cover glass for 24-48 hr.

Glass pipettes are pulled to a tip diameter of 1-2 micrometer on a pipette puller. The pipettes are filled with the intracellular solution and a chloridized silver wire is inserted along its length, which is then connected to the headstage of the voltage-clamp amplifier (Axon Instruments or HEKA electronik). The extracellular recording solution consists of (mM): 140 NaCl, 5 KCl, 2 CaCl₂, 1 MgCl₂, 10 HEPES, and 10 Glucose, pH 7.4 adjusted with NaOH. The internal solution consists of (mM): 120 CsF, 15 NaCl, 10 EGTA, and 10 HEPES, pH 7.2 adjusted with CsOH; Upon insertion of the pipette tip into the bath, the pipette resistance is noted (acceptable range is between 1-3 megaohm). The junction potential between the pipette and bath solutions is zeroed on the amplifier. After establishing the whole-cell configuration, approximately 10 minutes are allowed for the pipette solution to equilibrate within the cell before beginning recording. Currents are lowpass filtered between 2-5 kHz and digitally sampled at 10 kHz.

The normalized steady-state inactivation curve is constructed using 2 sec (for vehicle) or 60 sec (for drugs) conditioning pulse to different potentials followed immediately by the test pulse to −10 mV. Peak currents are plotted as fraction of the maximum current at the conditioning potentials ranging from −120 mV to −40 mV for Na_(v1.3) and from −130 mV to −60 mV for Na_(v1.7). V1/2 or k values are estimated from Boltzmann fits. The affinity of drugs to resting state of Na channels (K_(resting) or K_(r)) is assessed by 30 msec test pulse from a negative holding potential of -120 or −130 mV, where virtually all channels are in the resting state. K_(r) value is calculated by a conventional 1:1 binding model: K _(resting)(K _(r))={[drug]I _(max),drug/(I _(max),control−I _(max),drug)}  [Math.2]

-   -   where K_(resting)(=K_(r)) is a dissociation constant for the         resting state and [drug] is compound concentration.         I_(max),control and I_(max),drug are peak currents in the         absence and presence of compound, respectively.

The affinity of drug to inactivated state of Na channels (K_(inact) or K_(i)) is estimated from the shift of the availability curve by compound. Interaction of the compound with the channel on inactivated state is evaluated by the following equation: K _(inact)(K _(i))={[drug]/((1+[drug]/Kr)*exp(−

V/k)−1)}  [Math.3] where K_(inact)(=K_(i)) is a dissociation constant for the inactivated state.

V is the compound-induced voltage shift of half maximal voltage of Boltzmann curve and k is the slop factor on presense of compound.

All tested compounds of the invention show potent activities in this model. For example, the activities (Ki) of example 2 against Nav_(1.3) and Nav_(1.7) are 0.57 microM and 0.34 microM, respectively.

In Vivo Assay

Chronic Constriction Injury (CCI)-Induced Static Allodynia in Rats

Male Sprague-Dawley rats at 7 weeks old are purchased from Charles River Japan Inc., and housed in groups of two per cage under a 12-h light/dark cycle (lights on at 07:00) with access to food and water ad libitum. CCI-induced static allodynia is assessed by von Frey hair (VFH) test. Surgery is performed according to the method of Bennett G J and Xie Y K (Pain 1988, 33: 87-107). The animals are anesthetized with intraperitoneal injection of pentobarbital sodium. The left common sciatic nerve is exposed at the level of the middle of the thigh, freed of adhering tissue, and four ligatures are loosely tided around it by using 4-0 silk thread. The incision is sutured, and the rats are allowed to recover in their cages with soft bedding. Sham operation is performed in the same manner except of sciatic nerve ligation. The animals are individually placed in a Plexiglas test chamber on an elevated grid to acclimate before the day of testing. On postoperative day (POD) 14-28, evaluation is performed using a series of calibrated VFH (Semmes-Winstein monofilaments) with 0.4, 0.6, 1, 2, 4, 6, 8 and 15 g force. VFH starting with the 2 g force is applied in an ascending or descending fashion according to a modified Dixon up-down method described by Chaplan SR et al. (J Neurosci Methods 1994, 53: 55-63). Each VFH is presented to the plantar surface of the operated hind paw with steady upward pressure until bent for approximately 6 seconds. In the absence of a paw withdrawal, a stronger stimulus is presented. In the event of a paw withdrawal, the next weaker stimulus is chosen. After the initial change from positive to negative or vice versa 4 more stimulations are applied. The 6-score pattern of positive and negative responses is converted into a 50% paw withdrawal threshold (PWT) using the following formula: 50% PWT(g)=(10^([Xf+κδ]))/10,000  [Math.4] where Xf is the value (in log units) of the final VFH used, κ is the tabular value for the pattern of positive/negative responses and δ is the mean difference between stimuli in log units (here, 0.224).

In the cases where continuous positive or negative responses are observed all the way out to the end of the stimulus spectrum, values of 0.25 and 15 g are assigned, respectively. The animals showing static allodynia (<4 g of 50% PWT) by CCI surgery are selected for evaluation and randomized to be nearly equal mean 50% PWT across all groups. The compounds of the invention or their vehicles are administered systemically. The rats are habituated to the chamber for at least 20 minutes before the measurement. The 50% PWT is measured at the appropriated time after compound administration. Statistical analysis is performed by unpaired t-test or one-way analysis of variance (ANOVA) with Dunnett's post-hoc test compared to the vehicle group.

All tested compounds of the invention show potent activities in this model.

Complete Freund's Adjuvant (CFA)-Induced Thermal Hyperalgesia in Rats

Male Sprague-Dawley rats at 6 weeks old are purchased from Charles River Japan Inc., and housed in groups of two per cage under a 12-h light/dark cycle (lights on at 07:00) with access to food and water ad libitum. CFA-induced thermal hyperalgesia is assessed using the plantar test apparatus (Ugo Basile) as described by Hargreaves K et al. (Pain 1988, 32: 77-88). The animals are placed in an apparatus consisting of individual testing box on an elevated glass table and allowed to acclimate for at least 10 minutes. Following the habituation, a mobile radiant heat source is located under the table and heat stimulation is applied to the plantar surface of the right hind paw. The latency to remove its hind paw is defined as paw withdrawal latency (PWL) in sec. The cut-off point is set at 30 seconds to prevent tissue damage. CFA is prepared at a concentration of 2-3 mg/mL of Mycobacterium tuberculosis H37 RA in liquid paraffin. After disinfections with 70% ethanol, the rats are injected intraplantarly with 100 microL of CFA (200-300 microgram) into the right hind paw. Two days after CFA injection, PWL is measured in the same manner as mentioned above. The animals showing decrease of the PWL (hyperalgesia) by CFA injection are selected for evaluation and randomized to be nearly equal mean PWL across all groups. The compounds of the invention or their vehicles are administered systemically. The rats are habituated to the apparatus for at least 10 minutes before each measurement. The PWL is measured at the appropriated time after compound administration. Statistical analysis is performed by unpaired t-test or ANOVA with Dunnett's post-hoc test compared to the vehicle group.

All tested compounds of the invention show potent activities in this model.

CFA-Induced Weight Bearing Deficit in Rats

Male Sprague-Dawley rats at 7 weeks old are purchased from Charles River Japan Inc., and housed in groups of two per cage under a 12-h light/dark cycle (lights on at 07:00) with access to food and water ad libitum. CFA-induced weight bearing (WB) deficit is assessed using Incapacitance tester (Linton Instrumentation). The animals are habituated to a plastic case that comes with Incapacitance tester before the day of CFA injection. On the day of CFA injection, the weight distribution of each hind paw is measured 3 times per rat using the tester, and the difference of weight distribution, weight on the right (injected) paw minus weight on left (non-injected) paw, is defined as WB deficit value in g. The duration of the each measurement is adjusted to 3 seconds. CFA is prepared at a concentration of 2-3 mg/mL of Mycobacterium tuberculosis H37 RA in liquid paraffin. After disinfections with 70% ethanol, the rats are injected intraplantarly with 100 microL of CFA (200-300 microgram) into the right hind paw. Two days after CFA injection, the weight distribution of each hind paw is measured and the WB deficit value is calculated in the same manner as mentioned above. The animals showing decrease of the WB deficit (>30%) by CFA injection are selected for evaluation and randomized to be nearly equal across all groups. The compounds of the invention or their vehicles are administered systemically. The weight distribution of each hind paw is measured at the appropriated time after compound administration, and the WB deficit value is calculated as previously explained. Statistical analysis is performed by unpaired t-test or ANOVA with Dunnett's post-hoc test compared to the vehicle group.

All tested compounds of the invention show potent activities in this model.

Paw Incision-Induced Static Allodynia in Rats

Male Sprague-Dawley rats at 7 weeks old are purchased from Charles River Japan Inc., and housed in groups of two per cage under a 12-h light/dark cycle (lights on at 07:00) with access to food and water ad libitum. Paw incision-induced static allodynia is assessed by VFH test. Surgery is performed according to the procedure described by Brennan et al. (Pain 1996, 64: 493-501). The animals are initially anesthetized with 3-4% isoflurane/O₂ mixture in an anesthetic chamber and maintained with 2-3% delivered through a nose cone. The plantar surface of the right hind paw is sterilized with 7.5% povidone-iodine solution. A 1-cm longitudinal incision is made with a number 11 blade, through skin and fascia of the plantar aspect of the paw, starting 0.5 cm from the proximal edge of the heel and extending toward the toes. The plantaris muscle is elevated using forceps and retracted. The muscle origin and insertion remain intact. After hemostasis with gentle pressure, the skin is apposed with 2 sutures of 5-0 nylon. The wound site is covered with Terramycin ointment, and the rats are allowed to recover in their cages with soft bedding. The animals are individually placed in a Plexiglas test chamber on an elevated grid to acclimate for 1 hour before the day of surgery. On POD1, evaluation is performed using a series of calibrated VFH (0.008, 0.02, 0.04, 0.07, 0.16, 0.4, 0.6, 1, 1.4, 2, 4, 6, 8, 10, 15 and 26 g). Starting with the 0.16 g force in an ascending or descending fashion, each VFH is presented to the proximal end of the wound near the lateral heel with steady upward pressure until bent for approximately 6 seconds. In the absence of a paw withdrawal (negative response), a stronger stimulus is presented. In the event of a paw withdrawal (positive response), the next weaker stimulus is chosen. The lowest amount of force required to elicit two positive responses is defined as PWT in g. In the cases where continuous positive or negative responses are observed all the way out to the end of the stimulus spectrum, values of 0.008 and 26 g are assigned, respectively. The animals showing <1.4 g of PWT by incisional surgery are selected for evaluation and randomized to be nearly equal median PWT across all groups. The compounds of the invention or their vehicles are administered systemically. The rats are habituated to the chamber for at least 20 minutes before the measurement. The PWT is measured at the appropriated time after compound administration. Statistical analysis is performed by Mann-Whitney U-test or Kruskcal-Wallis with Dunn's post-hoc test compared to the vehicle group.

All tested compounds of the invention show potent activities in this model.

Paclitaxel-Induced Static Allodynia in Rats

Male Sprague-Dawley rats at 7 weeks old are purchased from Charles River Japan Inc., and housed in groups of two per cage under a 12-h light/dark cycle (lights on at 07:00) with access to food and water ad libitum. Paclitaxel-induced static allodynia is assessed by VFH test. Treatment of paclitaxel is performed according to the method of Polomano R C et al. (Pain 2001, 94: 293-304). Paclitaxel (2 mg) is injected intraperitoneally on four alternate days (Days 1, 3, 5 and 7) in a volume of 1 mL/kg. Cumulative dose is 8 mg/kg. In sham group, the vehicle (a mixture of 16.7% Cremophor EL and 16.7% ethanol in saline) is treated as the same schedule. The animals are individually placed in a Plexiglas test chamber on an elevated grid to acclimate before the day of testing. On Days 15-29, evaluation is performed using a series of calibrated VFH with 0.4, 0.6, 1, 2, 4, 6, 8 and 15 g force. VFH starting with the 2 g force is applied in an ascending or descending fashion according to a modified Dixon up-down method described by Chaplan S R et al. (J Neurosci Methods 1994, 53: 55-63). Each VFH is presented to the plantar surface of the operated hind paw with steady upward pressure until bent for approximately 6 seconds. In the absence of a paw withdrawal, a stronger stimulus is presented. In the event of a paw withdrawal, the next weaker stimulus is chosen. After the initial change from positive to negative or vice versa 4 more stimulations are applied. The 6-score pattern of positive and negative responses is converted into a 50% PWT using the following formula: 50% PWT(g)=(10^([Xf+κδ]))/10,000  [Math.5] where Xf is the value (in log units) of the final VFH used, κ is the tabular value for the pattern of positive/negative responses and δ is the mean difference between stimuli in log units (here, 0.224).

In the cases where continuous positive or negative responses are observed all the way out to the end of the stimulus spectrum, values of 0.25 and 15 g are assigned, respectively. The animals showing static allodynia (<4 g of 50% PWT) by paclitaxel treatment are selected for evaluation and randomized to be nearly equal mean 50% PWT across all groups. The compounds of the invention or their vehicles are administered systemically. The rats are habituated to the chamber for at least 20 minutes before the measurement. The 50% PWT is measured at the appropriated time after compound administration. Statistical analysis is performed by unpaired t-test or ANOVA with Dunnett's post-hoc test compared to the vehicle group.

All tested compounds of the invention show potent activities in this model.

Formalin-Induced Nociceptive Behaviors in Rats

Male Sprague-Dawley rats at 6 weeks old are purchased from Charles River Japan Inc., and housed in groups of two per cage under a 12-h light/dark cycle (lights on at 07:00) with access to food and water ad libitum. Formalin test is performed during the light cycle. The animals are acclimated to the testing chamber for at least 30 minutes prior to formalin injection. A mirror is placed behind and/or under the chamber to aid observation. The 50 microL of 5% formalin solution is injected subcutaneously into the plantar surface of the right hind paw. Immediately after the injection, the rats are individually placed in the chamber, and the pain-related behaviors are recorded. After the testing, the time spent licking and/or biting of the injected paw are counted in 5-minutes bins for 45 minutes following the formalin treatment. The sum of time spent licking/biting in seconds from time 0 to 5 minutes is considered as the early phase, whereas the late phase is taken as the sum of time spent licking/biting typically from 15 to 45 minutes. The compounds of the invention or their vehicles are administered systemically at the appropriated time point before the formalin injection. Statistical analysis is performed by unpaired t-test or ANOVA with Dunnett's post-hoc test compared to the vehicle group.

All tested compounds of the invention show potent activities in this model.

Human Dofetilide Binding Assay

Human HERG transfected HEK293S cells are prepared and grown in-house. The collected cells are suspended in 50 mM Tris-HCl (pH 7.4 at 4° C.) and homogenized using a hand held Polytron PT 1200 disruptor set at full power for 20 sec on ice. The homogenates are centri-fuged at 48,000×g at 4° C. for 20 min. The pellets are then resuspended, homogenized, and centrifuged once more in the same manner. The final pellets are resuspended in an appropriate volume of 50 mM Tris-HCl, 10 mM KCl, 1 mM MgCl₂ (pH 7.4 at 4° C.), homogenized, ali-quoted and stored at −80° C. until use. An aliquot of membrane fractions is used for protein concentration determination using BCA protein assay kit (PIERCE) and ARVOsx plate reader (Wallac). Binding assays are conducted in a total volume of 30 microL in 384-well plates. The activity is measured by PHERAstar (BMG LABTECH) using fluorescence polarization technology. Ten microL of test compounds are incubated with 10 microL of fluorescence ligand (6 nM Cy3B tagged dofetilide derivative) and 10 microL of membrane homogenate (6 microgram protein) for 120 minutes at room temperature. Nonspecific binding is determined by 10 microM E4031 at the final concentration.

All tested compounds of the invention show higher IC₅₀ values in human dofetilide binding than IC₅₀ values in Na_(v1.3) or Na_(v1.7) FRET Assay. The high IC₅₀ values in human dofetilide binding activities lead to reducing the risk of cardiovascular adverse events.

Metabolic Stability Assay:

Half-Life in Human Liver Microsomes (HLM)

Test compounds (1 microM) are incubated with 3.3 mM MgCl₂ and 0.78 mg/mL HLM (HL101) or 0.74 mg/mL HLM (Gentest UltraPool 150) in 100 mM potassium phosphate buffer (pH 7.4) at 37° C. on the 96-deep well plate. The reaction mixture is split into two groups, a non-P450 and a P450 group. NADPH is only added to the reaction mixture of the P450 group. (NADPH generation system is also used instead of NADPH.) An aliquot of samples of P450 group is collected at 0, 10, 30, and 60 min time point, where 0 min time point indicated the time when NADPH is added into the reaction mixture of P450 group. An aliquot of samples of non-P450 group is collected at -10 and 65 min time point. Collected aliquots are extracted with acetonitrile solution containing an internal standard. The precipitated protein is spun down in centrifuge (2000 rpm, 15 min). The compound concentration in supernatant is measured by LC/MS/MS system.

The half-life value is obtained by plotting the natural logarithm of the peak area ratio of compounds/internal standard versus time. The slope of the line of best fit through the points yield the rate of metabolism (k). This is converted to a half-life value using following equations: Half-life=ln 2/k

The compounds of this invention show preferable stability, which show the above-mentioned practical use.

Drug-Drug Interaction Assay

This method essentially involves determining the percent inhibition of metabolites formation from probes (Tacrine (Sigma A3773-1G) 2 microM, Dextromethorphan (Sigma D-9684) 5 microM, Diclofenac (Sigma D-6899-10G) 5 microM, and Midazolam(ULTRAFINE UC-429) 2 microM) at 3 microM of the each compound.

More specifically, the assay is carried out as follows. The compounds (60 microM, 10 microL) are pre-incubated in 170 microL of mixture including 0.1 mg protein/mL human liver microsomes, 100 mM potassium phosphate buffer (pH 7.4), 1 mM MgCl₂ and probes as substrate for 5 min. Reaction is started by adding a 20 microL of 10 mM NADPH (20 microL of NADPH generating system, which consist of 10 mM NADP⁺, 50 mM DL-lsocitric acid and 10 U/mL Isocitric Dehydrogenase, is also used). The assay plate is incubated at 37° C. Acetonitrile is added to the incubate solution at appropriate time (e.g. 8 min).

The metabolites' concentration in the supernatant is measured by LC/MS/MS system.

The degree of drug-drug interaction is interpreted based on generation % of metabolites in the presence or absence of test compound.

The compounds of this invention show preferable results, which show the above-mentioned practical use.

Plasma Protein Binding Assay

Plasma protein binding of the test compound (1 microM) is measured by the method of equilibrium dialysis using 96-well plate type equipment. HTD96a(registeredtrademark), regenerated cellulose membranes (molecular weight cut-off 12,000-14,000, 22 mm×120 mm) are soaked for over night in distilled water, then for 15 minutes in 30% ethanol, and finally for 20 minutes in dialysis buffer (Dulbecco's phosphate buffered saline, pH7.4). Frozen plasma of human, Sprague-Dawley rats, and Beagle dogs are used. The dialysis equipment is assembled and added 150 microL of compound-fortified plasma to one side of each well and 150 microL of dialysis buffer to the other side of each well. After 4 hours incubation at 37° C. for 150 r.p.m, aliquots of plasma and buffer are sampled. The compound in plasma and buffer are extracted with 300 microL of acetonitrile containing internal standard compounds for analysis. The concentration of the compound is determined with LC/MS/MS analysis.

The fraction of the compound unbound is calculated by the following equation (A) or (B): fu=1−{([plasma]_(eq)−[buffer]_(eq))/([plasma]_(eq))}  (A)

wherein [plasma]_(eq) and [buffer]_(eq) are the concentrations of the compound in plasma and buffer, respectively.

$\begin{matrix} \left\lbrack {{Math}.\mspace{11mu} 6} \right\rbrack & \; \\ {{{fu}(\%)} = {\frac{{{Cb}\text{/}{Cis}},{b \times 4}}{{{Cp}\text{/}{Cis}},{p \times 4\text{/}3}} \times 100}} & (B) \end{matrix}$

wherein Cp is the peak area of the compound in plasma sample;

Cis,p is the peak area of the internal standard in plasma sample;

Cb is the peak area of the compound in buffer sample;

Cis,b is the peak area of the internal standard in buffer sample;

4 and 4/3 is the reciprocal of the dilution rate in plasma and buffer, respectively.

The compounds of this invention show preferable plasma protein binding, which show the above-mentioned practical use.

Equilibrium Aqueous Solubility Study

The DMSO solution (2 microL, 30 mM) of each compound is dispensed into each well of a 96-well glass bottom plate. Potassium phosphate buffer solution (50 mM, 198 microL, pH 6.5) is added to each well, and the mixture is incubated at 37° C. with rotate shaking for 24 hours. After centrifugation at 2000 g for 5 minutes, the supernatant is filtered through the polycarbonate iso-pore membrane. The concentration of samples is determined by a general gradient HPLC method (J. Pharm. Sci. 2006, 95, 2115-2122).

All publications, including but not limited to, issued patents, patent applications, and journal articles, cited in this application are each herein incorporated by reference in their entirety. Although the invention has been described above with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.

INDUSTRIAL APPLICABILITY

The pyrazolopyridine derivatives of the present invention are useful in the treatment of a wide range of disorders, particularly pain, such as acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain including post-surgical pain, and mixed pain types involving the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spine, urogenital system, cardiovascular system and CNS, including cancer pain, back pain, orofacial pain and chemo-induced pain. 

The invention claimed is:
 1. A compound of the following formula (I):

wherein: A is a 5 to 6-membered aromatic ring which may contain 0 to 3 heteroatoms independently selected from the group consisting of O, N and S, or a 9 to 10-membered bicyclic aromatic ring which may contain 0 to 2 heteroatoms independently selected from the group consisting of O, N and S; —B—C— is —NH—(C═O)— or —(C═O)—NH—; R¹ is independently selected from the group consisting of: (1) hydrogen, (2) —O_(n)—C₁₋₆ alkyl where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (3) —O_(n)—C₃₋₇ cycloalkyl where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (4) —O-_(n)-phenyl, —O-_(n)-pyridyl or —O-_(a)-pyrazolyl, wherein the phenyl, the pyridyl or the pyrazolyl is unsubstittned or substituted with one or more substituents independently selected from R¹¹, and (5) —NH—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹; wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of —O_(n)—; R² is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) —O_(n)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (5) —O_(n)—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, and (6) —O_(n)-phenyl, where the phenyl is unsubstituted or substituted with ore or more substituents independently selected from R⁷; wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of —O_(n)—; p is 1, 2, 3, or 4; when p is two or more than two, R² may be same or different; R³ and R⁴ are independently hydrogen or C₁₋₆ alkyl; R⁵ is independently selected from die group consisting of: (1) hydrogen, (2) halogen, and (3) —O_(n)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷; wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of —O_(n)—; R⁵ may be anywhere on the pyrazolopyridine ring; q is 1, 2 or 3; when q is two or more than two, R⁵ may be the same or different; R⁶ is independently hydrogen, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, —NR⁸R⁹, heterocyclyl, aryl, aryl-C₁₋₆ alkyl, or heterocyclyl-C₁₋₆ alkyl, wherein the C₁₋₆ alkyl, the C₁₋₆ alkoxy, the C₃₋₇ cycloalkyl, the heterocyclyl, the aryl, the aryl-C₁₋₆ alkyl, or the heterocyclyl-C₁₋₆ alkyl, is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —C₃₋₇ cycloalkyl, hydroxyl-C₁₋₆ alkoxy, —CN, —NR⁸R⁹, —(C═O)—R⁸, —(C═O)—NR⁸R⁹, —NR⁸—(C═O)—R⁹, —NR⁸—(C═O)—OR⁹, —NR⁸—S(O)₂—R⁹, and —S(O)₂—R⁸; R⁷ is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, and (8) —(C═O)_(m)—O_(l)-phenyl wherein the phenyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹; wherein l is 0 or 1 and m is 0 or 1; when l is 0 or m is 0, a chemical bond is present in the place of —O_(l)— or —(C═O)_(m)—, and when l is 0 and m is 0, a chemical bond is present in the place of —(C═O)_(m)—O_(l)—; R⁸ and R⁹ are independently hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, or aryl, wherein the C₁₋₆ alkyl, the C₃₋₇ cycloalkyl, or the aryl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen and hydroxyl; or R⁸ forms a 4 to 7 membered ring with R⁹ which may contain a nitrogen atom, an oxygen atom, a sulfur atom or a double bond, wherein the 4 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of:(1) hydrogen, (2) hydroxyl, and (3) halogen; R¹¹ is independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C₁₋₆ alkyl, wherein the alkyl is unsubstituted or substituted with one or more halogens, (5) C₃₋₆ cycloalkyl, and (6) —O—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more, halogens; k is 1 or 2; and r is 0 or 1, when r is 0, a chemical bond is present in the place of —[O]_(r)—; wherein, in the R⁶, R⁸ and R⁹, the aryl is independently a 5 to 6-membered aromatic ring which may contain 0 to 3 heteroatoms independently selected from the group consisting of O, N and S; and wherein the heterocyclyl is a saturated 4 to 10-membered ring which may contain 1 to 2 heteroatoms independently selected from the group consisting of O, N and S; or a pharmaceutically acceptable salt thereof.
 2. The compound described in claim 1 wherein k is 1; r is 0; or a pharmaceutically acceptable salt thereof.
 3. A compound of the following formula (II)

wherein: A is a 5 to 6-membered aromatic ring which may contain 0 to 3 heteroatoms independently selected from the group consisting of O, N and S, or a 9 to 10-membered bicyclic aromatic ring which may contain 0 to 2 heteroatoms independently selected from the group consisting of O, N and S; R¹ is independently selected from the group consisting of: (1) hydrogen (2) —O_(n)—C₁₋₆ alkyl where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (3) —O_(n)—C₃₋₇ cycloalkyl where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (4) —O-_(n)-phenyl, —O-_(n)-pyridyl or —O-_(n)-pyrazolyl, wherein the phenyl, the pyridyl or the pyrazolyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹; wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of —O_(n)—; R² is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) —O_(n)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (5 ) —O_(n)—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, and (6) —O_(n)-phenyl, where the phenyl is unsubstituted or substituted with one or more substituents independently selected from R⁷; wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of —O_(n)—; p is 1, 2, 3, or 4; when p is two or more than two, R² may be the same or different; R³ and R⁴ are independently hydrogen or C₁₋₆ alkyl; R⁵ is independently selected from the group consisting of: (1) hydrogen, (2) halogen, and (3) —O_(n)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷; wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of —O_(n)—; R⁵ may be anywhere on the pyrazolopyridine ring; q is 1, 2 or 3; when q is two or more than two, R⁵ may be the same or different; R⁶ is independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, 13 NR⁸R⁹, heterocyclyl, aryl, aryl-C₁₋₆ alkyl, or heterocyclyl-C₁₋₆ alkyl, wherein the C₁₋₆ alkyl, the C₁₋₆ alkoxy, the C₃₋₇ cycloalkyl, the heterocyclyl, the aryl, the aryl-C₁₋₆ alkyl, or the heterocyclyl-C₁₋₆ alkyl, is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —C₃₋₇ cycloalkyl, —CN, —(C═O)—R⁸, —(C═O)—NR⁸R⁹,—NR⁸—(C═O)—R⁹, and —S(O)₂—R⁸; R⁷ is selected from theroup consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, and (8) —(C═O)_(m)—O_(l)-phenyl wherein the phenyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹; wherein l is 0 or 1 and m is 0 or 1; when l is 0 or m is 0, a chemical bond is present in the place of —O_(l)— or —(C═O)_(m)— and when l is 0 and m is 0, a chemical bond is present in the place of —(C═O)_(m)—O_(l); R⁸ and R⁹ are independently hydrogen, C₁₋₆ alkyl, Chd 3-7 cycloalkyl, or aryl, wherein the C₁₋₆ alkyl, the C₃₋₇ cycloalkyl, or the aryl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen and hydroxyl; or R⁸ forms a 4 to 7 membered ring with R⁹ which may contain a nitrogen atom, an oxygen atom, a sulfur atom or a double bond, wherein the 4 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, and (3) halogen; R¹¹ is independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) —C₁₋₆, alkyl, where the alkyl is unsubstituted or substituted with one or more halogens (5) cycloalkyl, (6) —O—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more halogens; wherein, in the R⁶, R⁸ and R⁹, the aryl is independently a 5 to 6-membered aromatic ring which may contain 0 to 3 heteroatoms independently selected from the group consisting of O, N and S; and wherein the heterocyclyl is a saturated 4 to 10-membered ring which may contain 1 to 2 heteroatoms independently selected from the group consisting of O, N and S; or a pharmaceutically acceptable salt thereof.
 4. The compound according to claim 3, wherein: R² is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) methyl, and (4) methoxy; p is 1; R³ is hydrogen; R⁴ is hydrogen or methyl; and R⁶ is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, heterocyclyl, aryl, and aryl-C₁₋₆ alkyl, wherein the methyl, the ethyl, the isopropyl, the cyclopropyl, the heterocyclyl, the aryl, or the aryl-C₁₋₆ alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, and —CN; wherein the aryl is independently selected from the group consisting of pyridyl, oxazolyl, isoxazolyl and thiazolyl; and wherein the heterocyclyl is selected from the group consisting of piperidinyl, pyrrolidinyl, tetrahydrofuranyl and tetrahydropyranyl; or a pharmaceutically acceptable salt thereof.
 5. A compound of the following formula (III)

wherein: A is a 5 to 6-membered aromatic ring which may contain 0 to 3 heteroatoms independently selected from the group consisting of O, N and S, or a 9 to 10-membered bicyclic aromatic ring which may contain 0 to 2 heteroatoms independently selected from the group consisting of O, N and S; R¹ is independently selected from the group consisting of: (1) hydrogen, (2) —O_(n)—C₁₋₆ alkyl where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (3) —O_(n)—C₃₋₇ cycloalkyl where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (4) —O-_(n)-phenyl, —O-_(n)-pyridyl or —O-_(n)-pyrazolyl, wherein the phenyl, the pyridyl or the pyrazolyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, and (5) —NH—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹; wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of —O_(n)—; R² is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) —O_(n)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (5) —O_(n)—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, and (6) —O_(n)-phenyl, where the phenyl is unsubstituted or substituted with one or more substituents independently selected from R⁷; wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of —O_(n)—; p is 1, 2, 3, or 4; when p is two or more than two, R² may be the same or different; R³ and R⁴ are independently hydrogen or C₁₋₆ alkyl; R⁵ is independently selected from the group consisting of: (1) hydrogen, (2) halogen, and (3) —O_(n)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷; wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of —O_(n)—; R⁵ may be anywhere on the pyrazolopyridine ring; q is 1, 2 or 3; when q is two or more than two, R⁵ may be the same or different; R⁶ is independently hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, aryl, aryl-C₁₋₆ alkyl, or heterocyclyl-C₁₋₆ alkyl, wherein the C₁₋₆ alkyl, the C₃₋₇ cycloalkyl, the heterocyclyl, the aryl, the aryl-C₁₋₆ alkyl, or the heterocyclyl-C₁₋₆ alkyl, is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —C₃₋₇ cycloalkyl, —O—C₃₋₇ cycloalkyl, hydroxyl-C₁₋₆ alkoxy, —CN, —NR⁸R⁹, —(C═O)—R⁸, —(C═O)—NR⁸R⁹, —NR⁸—(C═O)—R⁹, —NR⁸—(C═O)—OR⁹, —NR⁸—S(O)₂—R⁹; and —S(O)₂—R⁸; R⁷ is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, and (8) —(C═O)_(m)—O_(l)-phenyl where the phenyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹; wherein l is 0 or 1 and m is 0 or 1; when l is 0 or m is 0, a chemical bond is present in the place of —O_(l)— or —(C═O)_(m)—, and when l is 0 and m is 0, a chemical bond is present in the place of —(C═O)_(m)—O_(l)—; R⁸ and R⁹ are independently hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, or aryl, wherein the C₁₋₆ alkyl, the C₃₋₇ cycloalkyl, or the aryl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen and hydroxyl; or R⁸ forms a 4 to 7 membered ring with R⁹ which may contain a nitrogen atom, an oxygen atom, a sulfur atom or a double bond, wherein the 4 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, and (3) halogen; R¹¹ is independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) —C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more halogens, (5) —C₃₋₆ cycloalkyl, and (6) —O—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more, halogens; wherein, in the R⁶, R⁸ and R⁹, the aryl is independently a 5 to 6-membered aromatic ring which may contain 0 to 3 heteroatoms independently selected from the group consisting of O, N and S; and wherein the heterocyclyl is a saturated 4 to 10-membered ring which may contain 1 to 2 heteroatoms selected from the group consisting of O, N and S; or a pharmaceutically acceptable salt thereof.
 6. The compound described in claim 5 wherein: R² is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) methyl, and (4) methoxy; p is 1; R³ is hydrogen; R⁴ is hydrogen or methyl; R⁶ is selected from the group consisting of methyl, ethyl, isopropyl, propyl, and butyl wherein the methyl, the ethyl, the isopropyl, the propyl, or the butyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, —O—C₁₋₆ alkyl, —CN, and —NR⁸—(C═O)—R⁹ in which each of R⁸ and R⁹ is as defined in claim 5; or a pharmaceutically acceptable salt thereof.
 7. A compound which is selected from the group consisting of: N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; 2-hydroxy-2-methyl-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)acetamide; N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)acetamide; N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propionamide; N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)acetamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propionamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; N-(2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propionamide; N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)acetamide; N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propionamide; N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)acetamide; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)oxazole-5-carboxamide; 1,1-dimethyl-3-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)urea; 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-amine; ethyl (2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)carbamate; N-(2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)acetamide; N-(2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propionamide; 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((6-(2,2-difluoroethoxy)-5-fluoropyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((6-(2,2-difluoroethoxy)-5-fluoropyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propionamide; N-(2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)pivalamide; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)nicotinamide; N-(2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; 3-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-1,1-dimethylurea; N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)pivalamide; N-(2-(4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-(4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(4-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(tetrahydrofuran-3-yl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-cyclopropyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-cyclobutyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(cyclopropylmethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-methoxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-N-(1-hydroxypropan-2-yl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propionamide; N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(2-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((6-(4-fluorophenoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((6-(4-fluorophenoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; (S)-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)tetrahydrofuran-2-carboxamide; (S)-N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)tetrahydrofuran-2-carboxamide; N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)nicotinamide; (R)-2-hydroxy-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; (S)-2-hydroxy-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)pyrrolidine-1-carboxamide; 1-acetyl-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)piperidine-4-carboxamide; N-isopropyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-propyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isobutyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-ethoxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(cyanomethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-((tetrahydrofuran-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-(dimethylamino)ethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(pyridin-3-ylmethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(pyridin-3-yl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)tetrahydrofuran-2-carboxamide; (R)-N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)tetrahydrofuran-2-carboxamide; N-(3-methoxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-((1-hydroxycyclohexyl)methyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propionamide; N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; 2-hydroxy-2-methyl-N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; N-(7-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propionamide; N-(7-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; 2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 1-isobutyryl-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)piperidine-4-carboxamide; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-1-(methylsulfonyl)piperidine-4-carboxamide; (S)-1-acetyl-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)pyrrolidine-2-carboxamide; (R)-1-acetyl-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)pyrrolidine-2-carboxamide; N-methyl-N-(2-((2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)amino)-2-oxoethyl)acetamide; (S)-2-methoxy-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; (S)-N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-methoxypropanamide; (R)-N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxypropanamide; (S)-N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxypropanamide; 2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-cyclopropyl-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(cyclopropylmethyl)-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-morpholinoethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-(pyridin-2-yl)acetamide; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-(pyridin-3-yl)acetamide; N-isopropyl-2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-cyclopropyl-2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(cyclopropylmethyl)-2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-(pyridin-4-yl)acetamide; N-(cyanomethyl)-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-propyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-cyanopropan-2-yl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxy-2-methylpropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-(dimethylamino)propyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-aminoethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(oxetan-3-yl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-((4-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((4-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-(pyridin-4-yl)acetamide; 2-(pyridin-4-yl)-N-(2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)acetamide; N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-(pyridin-3-yl)acetamide; 2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((4-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; 2-hydroxy-2-methyl-N-(2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; N-methyl-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-(2-methylthiazol-4-yl)acetamide; N-(2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-(pyridin-3-yl)acetamide; N-(2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-(pyridin-4-yl)acetamide; 2-(3,5-dimethylisoxazol-4-yl)-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)acetamide; N-isopropyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-N-(2,3-dihydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; 2-hydroxy-2-methyl-N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; N-methyl-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-N-(1-hydroxypropan-2-yl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-amino-2-oxoethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-(methylsulfonamido)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-cyanoethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-cyanoethyl)-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; 2-((5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-(2-hydroxyethoxy)ethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-ethyl-2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-N-(2,3-dihydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(4-fluorophenoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-((6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-N-(1-amino-1-oxopropan-2-yl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-(methylamino)-2-oxoethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-amino-3-oxopropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxy-2,2-dimethylpropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(4-hydroxybutyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-acetamidopropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-(methylsulfonamido)propyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(3-hydroxypropyl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(4-fluorophenoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; (S)-N-(2-hydroxypropyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-N-(2-hydroxypropyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-N-(2,3-dihydroxypropyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-N-(2,3-dihydroxypropyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-N-(2,3-dihydroxypropyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-((1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-N-(2-hydroxypropyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-N-(2-hydroxypropyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-N-(1-hydroxypropan-2-yl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-N-(1-hydroxypropan-2-yl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-cyanoethyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-cyanoethyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-amino-2-oxoethyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-methoxyethyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-methyl-6-(2-(2,2,2-trifluoroethoxy)ethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((5-methyl-6-(2-(2,2,2-trifluoroethoxy)ethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; 2-hydroxy-2-methyl-N-(2-((5-methyl-6-(2-(2,2,2-trifluoroethoxy)ethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; N-(2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-hydroxyethyl)-2-((5-methyl-6-(2-(2,2,2-trifluoroethoxy)ethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((5-methyl-6-(2-(2,2,2-trifluoroethoxy)ethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-((5-methyl-6-(2-(2,2,2-trifluoroethoxy)ethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((5-methyl-6-(2-(2,2,2-trifluoroethoxy)ethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((5-methyl-6-(2-(2,2,2-trifluoroethoxy)ethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-(2-(4-(trifluoromethyl)phenoxy)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-(2-(4-(trifluoromethyl)phenoxy)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-(2-(4-(trifluoromethyl)phenoxy)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(2-(4-(trifluoromethyl)phenoxy)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(2-(4-(trifluoromethyl)phenoxy)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; 2-(2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-cyclopropyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-cyclopropyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-cyclopropyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-cyclopropyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-cyclopropyl-6-(2,2,2-trifluoro ethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-((5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-methoxyethyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; N-(2-((5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; N,6-dimethyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-((6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-(3-methyl-4-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-(3-methyl-4-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(3-methyl-4-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(3-methyl-4-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-phenyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-methyl-2-(3-methyl-4-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(4-fluorophenoxy)-5-methylpyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((6-(4-fluorophenoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-N-(3-(methylsulfonyl)propyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-((1-(2,2,2-trifluoroethoxy)isoquinolin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((1-(2,2,2-trifluoroethoxy)isoquinolin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((1-(2,2,2-trifluoroethoxy)isoquinolin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((1-(2,2,2-trifluoroethoxy)isoquinolin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((1-(2,2,2-trifluoroethoxy)isoquinolin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-(4-((2,2,2-trifluoroethoxy)methyl)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-(4-((2,2,2-trifluoroethoxy)methyl)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-((1-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((1-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((1-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((1-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-(methylsulfonyl)propyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((5-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((5-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((5-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((5-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((1-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; N-(2-(3-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(3-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; 2-hydroxy-2-methyl-N-(2-(3-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; N-(2-(2-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(2-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-methyl-2-(3-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-(3-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(3-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(3-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-(2-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(2-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(2-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-(2,2,3,3,3-pentafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((5-(2,2,3,3,3-pentafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-hydroxyethyl)-2-(4-(1,1,2,2-tetrafluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(4-(1,1,2,2-tetrafluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((5-(2,2,3,3,3-pentafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((5-(2,2,3,3,3-pentafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((5-(2,2,3,3,3-pentafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; N-(2-((5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-acetamidoethyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-N-(2,3-dihydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-(3-(trifluoromethyl)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(3-(trifluoromethyl)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-methyl-2-(3-(trifluoromethyl)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-(3-(trifluoromethyl)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-(3-(trifluoromethyl)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(3-(trifluoromethyl)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-N-(2,3-dihydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-(4-(1,1,2,2-tetrafluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-(4-(1,1,2,2-tetrafluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-((S)-2-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2,3-dihydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2,3-dihydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(1-hydroxypropan-2-yl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; 2-hydroxy-2-methyl-N-(2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; N-methyl-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; 2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-N-(1-hydroxypropan-2-yl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; N-(2-((1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; 2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-methyl-2-((1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; 2-hydroxy-2-methyl-N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; 2-hydroxy-2-methyl-N-(2-(3-methyl-4-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; 2-hydroxy-2-methyl-N-(2-(2-(4-(trifluoromethyl)phenoxy)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; N-(2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; 2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-propionamidoethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-isobutyramidoethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-(cyclopropanecarboxamido)ethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; ethyl (2-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamido)ethyl)carbamate; N-(2-benzamidoethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-(2-hydroxy-2-methylpropanamido)ethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-(N-methylacetamido)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-butyramidoethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-(cyclobutanecarboxamido)ethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-(cyclohexanecarboxamido)ethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-(3-ethylureido)ethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(3-methyl-4-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((1-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-hydroxy-2-methyl-N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-(picolinamido)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-(nicotinamido)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-(isonicotinamido)ethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-(1-hydroxycyclohexanecarboxamido)ethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; 2-hydroxy-2-methyl-N-(2-((4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; N-(2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; N-methyl-2-((4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(2-(4-(trifluoromethyl)phenoxy)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((1-(2,2,2-trifluoroethoxy)isoquinolin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(4-(1,1,2,2-tetrafluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; 2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; 2-((6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; N-(2-((4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; 2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; 2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; 2-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; (R)-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(1-hydroxypropan-2-yl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(2,3-dihydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(2,3-dihydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-cyanoethyl)-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; 2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)oxazole-5-carboxamide; (S)-2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-((R)-2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-2-(4-(2,2-difluoroethoxy)-3,5-dimethylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-2-(3-(2,2-difluoroethoxy)-4-methylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-((R)-2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-((S)-2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-2-(4-(2,2-difluoroethoxy)-3,5-dimethylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-2-(3-(2,2-difluoroethoxy)-4-methylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-((S)-2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-((S)-2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoroethoxy)-3,5-dimethylbenzyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(3-(2,2-difluoroethoxy)-4-methylbenzyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoroethoxy)-3,5-dimethylbenzyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(3-(2,2-difluoroethoxy)-4-methylbenzyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(difluoromethoxy)-3-methylbenzyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(difluoromethoxy)-3-methylbenzyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(4-(difluoromethoxy)-3-methylbenzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(difluoromethoxy)-3-methylbenzyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(difluoromethoxy)-3-methylbenzyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-2-(4-(difluoromethoxy)-3-methylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-2-(4-(difluoromethoxy)-3-methylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; and 2-(4-(difluoromethoxy)-3-methylbenzyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; or a pharmaceutically acceptable salt thereof.
 8. The compound as claimed in claim 7, which is selected from the group consisting of: N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; 2-hydroxy-2-methyl-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)acetamide; N-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)acetamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)pivalamide; N-ethyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-methoxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-propyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-(dimethylamino)ethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-hydroxy-2-methyl-N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; 2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; 2-hydroxy-2-methyl-N-(2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; N-isopropyl-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-N-(2,3-dihydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-methyl-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-cyanoethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-cyanoethyl)-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-ethyl-2-((5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-(2-hydroxyethoxy)ethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-N-(2,3-dihydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(4-hydroxybutyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-acetamidopropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-(methylsulfonamido)propyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(3-hydroxypropyl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-N-(2-hydroxypropyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-N-(2-hydroxypropyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-N-(2,3-dihydroxypropyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-N-(2,3-dihydroxypropyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-N-(2-hydroxypropyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-N-(1-hydroxypropan-2-yl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-cyanoethyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-cyanoethyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((5-methyl-6-(2-(2,2,2-trifluoroethoxy)ethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-(2-(4-(trifluoromethyl)phenoxy)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(2-(4-(trifluoromethyl)phenoxy)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; 2-(2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-cyclopropyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-cyclopropyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-cyclopropyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; N,6-dimethyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(3-methyl-4-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(3-methyl-4-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((6-(4-fluorophenoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-N-(3-(methylsulfonyl)propyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-((1-(2,2,2-trifluoroethoxy)isoquinolin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((1-(2,2,2-trifluoroethoxy)isoquinolin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((1-(2,2,2-trifluoroethoxy)isoquinolin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(2,2,2-trifluoroethoxy)isoquinolin-4-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-(methylsulfonyl)propyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((1-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-hydroxyethyl)-2-(3-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-(2,2,3,3,3-pentafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-ethyl-2-((5-(2,2,3,3,3-pentafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; N-(2-((5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; N-(2-acetamidoethyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-N-(2,3-dihydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(3-(trifluoromethyl)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-N-(2,3-dihydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-(4-(1,1,2,2-tetrafluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-((S)-2-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(1-hydroxypropan-2-yl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; 2-hydroxy-2-methyl-N-(2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; N-methyl-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide; 2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-isopropyl-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-N-(1-hydroxypropan-2-yl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-hydroxy-2-methyl-N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; 2-hydroxy-2-methyl-N-(2-(3-methyl-4-(trifluoromethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; 2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-hydroxy-2-methyl-N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)propanamide; N-(2-acetamidoethyl)-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; 2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((6-cyclobutoxy-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; 2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-methyl-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-ethyl-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; 2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-(2-cyanoethyl)-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-methyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-ethyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-((R)-2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-2-(4-(2,2-difluoroethoxy)-3,5-dimethylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-((R)-2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (R)-2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-((S)-2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (S)-2-(4-(2,2-difluoroethoxy)-3,5-dimethylbenzyl)-N-(2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-((S)-2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-2-hydroxyethoxy)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoroethoxy)-3,5-dimethylbenzyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoroethoxy)-3,5-dimethylbenzyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoropropoxy)-3-methylbenzyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; 2-(4-(difluoromethoxy)-3-methylbenzyl)-N-(3-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; and 2-(4-(difluoromethoxy)-3-methylbenzyl)-N-isopropyl-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; or a pharmaceutically acceptable salt thereof.
 9. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof, according to claim 1, and a pharmaceutically acceptable carrier.
 10. The pharmaceutical composition according to claim 9, further comprising another pharmacologically active agent.
 11. A method for the treatment of a condition or disorder in which a TTX-S channel blocker is involved, in an animal or a human, which comprises administering to the animal or human in need of such treatment a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein the condition or disorder is selected from the group consisting of: acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain, multiple sclerosis, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, a functional bowel disorder, an inflammatory bowel disease, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, a cluster and tension headache, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia, Crohn's disease, epilepsy or an epileptic condition, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, myotonia, arrhythmia, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, breakthrough pain, postsurgical pain, stroke, cancer pain, seizure disorder, causalgia, chemo-induced pain, anxiety, and depression; and combination thereof.
 12. A process for preparing a pharmaceutical composition comprising mixing the compound or the pharmaceutically acceptable salt thereof according to claim 1, and a pharmaceutically acceptable carrier or excipient.
 13. The method according to claim 11, wherein the condition or disorder is anxiety or depression.
 14. The compound according to claim 1, wherein A is selected from the group consisting of pyridyl, pyridazinyl, phenyl, pyrazolyl, pyrazinyl, triazolyl, isoquinolyl, indolyl, and benzoimidazolyl; or a pharmaceutically acceptable salt thereof.
 15. A single enantiomer of a compound selected from the group consisting of: (1) N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; (2) N-(2-(1-(5-methyl -6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)acetamide; (3) N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2-pyrazolo[4,3-c]pyridin-4-yl)propionamide; (4) N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; (5) N-(2-hydroxyethy)-2H-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (6) N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (7) N-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxmide; (8) N-ethyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (9) N-methyl-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (10) N-ethyl-2-(1-(4-methyl-5-(2,2,2trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (11) N-(2-(1-(4-methyl-5-(2,2,2trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)isobutyramide; (12) 2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)-yl)propanamide; (13) 2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-((R)-2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (14) 2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-((S)-2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (15) 2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (16) 2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-hydroxypropyl)-2H-parazolo[4,3-c]pyridine-4-carboxamide; (17) 2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-carboxamide; (18) N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-2H-parazolo[4,3-c]pyridine-4-yl)cyclopropanecarboxamide; (19) N-isopropyl-2-(1-(5-methyl-5-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (20) N-(2-acetamidoethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (21) N-(2-hydroxyethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (22) N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (23) N-((S)-2-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (24) N-isopropyl-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (25) N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-yl)cyclopropanecarboxamide; (26) N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2H-pyrazolo[4,3-c]pyridine-4-yl)oxazole-5-carboxamide; (27) 2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-((R)-2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (28) 2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl -N-((S)-2-hydroxypropyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (29) 2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; (30) 2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]pyridine-4-carboxamide; and (34) N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridine-3-yl)ethyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cycopropanecarboxamide; or a pharmaceutically acceptable salt thereof. 